Acquired Immunodeficiency Syndrome: Apetrei C

Pandrea I, Silvestri G, Apetrei C. · Divisions of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, USA. · Curr HIV Res. · Pubmed #19149555 No free full text.

Abstract: It is generally considered that African nonhuman primates (NHPs) do not progress to AIDS. In the wild, due to either a shorter life span or an insufficient follow-up of the animals, no AIDS cases were described to date. However, in captivity, at least one case of immunodeficiency was reported for each of the currently available models of natural infection (African green monkey, sooty mangabey and mandrill). Furthermore, experimental infection of three other African NHP species, the black mangabey (BkM), the chimpanzee and the baboon with heterologous viruses, such as SIVsmm, HIV-1 and HIV-2, respectively also resulted in progression to AIDS. Here, we present the clinical, pathologic and virologic findings of these cases of progressive disease in African NHP hosts. Similar to pathogenic infections of humans and rhesus macaques, progression to AIDS in natural hosts is characterized by: CD4(+) T cell depletion in peripheral blood and intestine, opportunistic infections and neoplasia, severe weight loss, lymphocytic interstitial pneumonia, lymphoid tissue hypoplasia, and giant cell disease. Importantly, in these animals the set point levels of viral loads (VLs) were higher than in the majority of naturally-infected African NHPs, with significant increases of VLs occurring in association with disease progression. Finally, African NHP progressors showed increased levels of immune activation and cell proliferation, which differentiate them from the vast majority of African NHPs in which immune activation is not significantly increased during the chronic SIV infection compared to their SIV uninfected counterparts. Despite the rarity of AIDS cases in African NHPs, the spectrum and morphology of the observed lesions are very similar to those encountered in humans or macaques with AIDS. Therefore, we suggest that the "nonpathogenic" models of SIV infection should be reconsidered as "persistently nonprogressive" SIV infections. The fact that SIV-infected African NHPs may, in fact, occasionally progress to AIDS emphasizes the importance of studying these models to better understand AIDS pathogenesis and design new therapeutic and preventative interventions for HIV infection.

Pandrea I, Sodora DL, Silvestri G, Apetrei C. · Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433, USA. · Trends Immunol. · Pubmed #18676179 No free full text.

Abstract: Identifying distinctions between pathogenic HIV and simian immunodeficiency virus (SIV) infections and nonprogressive SIV in natural African primate hosts might provide key insights into HIV pathogenesis. Similar to pathogenic HIV infection in humans, natural SIV infections result in high viral replication and massive acute depletion of mucosal CD4(+) T cells. A key distinction of natural SIV infections is a rapidly developing anti-inflammatory milieu that prevents chronic activation, apoptosis and proliferation of T cells and preserves the function of other immune cell subsets, thus contributing to the integrity of the mucosal barrier and the lack of microbial translocation from the gut to the peritoneum. Immunologic features observed during natural SIV infections suggest approaches for designing new strategies for producing novel second-generation vaccines and therapeutic approaches to inhibit disease progression in HIV-infected humans.

Paiardini M, Frank I, Pandrea I, Apetrei C, Silvestri G. · Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, USA. · AIDS Rev. · Pubmed #18385779 No free full text.

Abstract: The mucosal immune system plays a central role in both the transmission of HIV infection and the pathogenesis of AIDS. Most HIV infections are acquired through mucosal transmission, and quantitative and qualitative defects of mucosal immunity are consistently present in all stages of pathogenic HIV and SIV infections. A series of recent studies has emphasized the role of a rapid, dramatic, and largely irreversible depletion of mucosa-associated lymphoid tissue-based memory CD4(+)CCR5(+) T-cells as a key determinant of disease progression in HIV-infected individuals and SIV-infected macaques. It has also been proposed that, in order to be effective, an AIDS vaccine should prevent the early depletion of these mucosal CD4(+) T-cells. However, the observation of depletion of mucosal CD4(+) T-cells during the primary phase of nonpathogenic SIV infection of natural SIV hosts, such as sooty mangabeys and African green monkeys, suggests that additional pathogenic factors are involved in the AIDS-associated mucosal immune dysfunction. These factors may include: (i) selective depletion of specific CD4(+) T-cell subsets; (ii) dysfunction of other (non-CD4(+)) immune cells; and (iii) generalized immune activation. Importantly, the mucosal immune dysfunction observed during pathogenic HIV and SIV infection is associated with translocation of microbial products (i.e. lipopolysaccharide) from the intestinal lumen to the systemic circulation where they may be responsible, at least in part, for the chronic immune activation that follows pathogenic HIV and SIV infections. The role of mucosal immunity in AIDS pathogenesis emphasizes the importance of understanding whether and to what extent the HIV-associated depletion of mucosal CD4(+) T-cells is reversible after prolonged suppression of virus replication with antiretroviral therapy. Further studies of mucosal immunity during primate lentiviral infections will be needed to better understand, and ultimately prevent and treat, the mechanisms underlying the AIDS-associated mucosal immune dysfunction.

VandeWoude S, Apetrei C. · Department of Microbiology, Immunology and Pathology, College of Veterinary and Biomedical Sciences, Colorado State University, Fort Collins, CO 80538-1619, USA. · Clin Microbiol Rev. · Pubmed #17041142 links to  free full text

Abstract: Over 40 nonhuman primate (NHP) species harbor species-specific simian immunodeficiency viruses (SIVs). Similarly, more than 20 species of nondomestic felids and African hyenids demonstrate seroreactivity against feline immunodeficiency virus (FIV) antigens. While it has been challenging to study the biological implications of nonfatal infections in natural populations, epidemiologic and clinical studies performed thus far have only rarely detected increased morbidity or impaired fecundity/survival of naturally infected SIV- or FIV-seropositive versus -seronegative animals. Cross-species transmissions of these agents are rare in nature but have been used to develop experimental systems to evaluate mechanisms of pathogenicity and to develop animal models of HIV/AIDS. Given that felids and primates are substantially evolutionarily removed yet demonstrate the same pattern of apparently nonpathogenic lentiviral infections, comparison of the biological behaviors of these viruses can yield important implications for host-lentiviral adaptation which are relevant to human HIV/AIDS infection. This review therefore evaluates similarities in epidemiology, lentiviral genotyping, pathogenicity, host immune responses, and cross-species transmission of FIVs and factors associated with the establishment of lentiviral infections in new species. This comparison of consistent patterns in lentivirus biology will expose new directions for scientific inquiry for understanding the basis for virulence versus avirulence.

Apetrei C, Marx PA. · Tulane National Primate Research Center, Covington, LA 70433, USA. · J Neurovirol. · Pubmed #15962455 No free full text.

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Marx PA, Apetrei C, Drucker E. · Tulane National Primate Research Center, Covington, LA, USA. · J Med Primatol. · Pubmed #15525322 No free full text.

Abstract: Based on findings demonstrating the simian ancestry of HIV, AIDS has been reported to be a zoonosis. However, this theory has never been proved and must seriously be questioned. Several arguments show that HIV-AIDS is not a zoonosis. (i) If AIDS were a zoonosis, there must be evidence of AIDS being directly acquired from an animal species, as is rabies, a disease that is directly acquired from animals. (ii) Despite long-term and frequent human exposure to SIV-infected monkeys in Africa, only 11 cross-species transmission events are known, and only four of these have resulted in significant human-to-human transmission, generating HIV-1 groups M and O and HIV-2 groups A and B. The closest relatives of SIVcpz (HIV-1 group N) and of SIVsm (HIV-2 groups C-H) are extremely rare, with only six HIV-1 group N-infected patients and only single individuals known to be infected by HIV-2 groups C-H. SIV, while capable of cross-species transmission, is thus poorly adapted for disease and epidemic spread. If AIDS were a zoonosis that is capable of significant human-to-human spread, there would be a plethora of founder subtypes and groups. (iii) Human exposure to SIV is thousands of years old, but AIDS emerged only in the 20th century. If AIDS were a zoonosis that spread into the human population, it would have spread to the West during slave trade. (iv) Experimental transmission of SIVs to different species of monkeys is often well controlled by the new host, showing that the virus and not the disease is transmitted. Therefore, we conclude that cross-species transmission of SIV does not in itself constitute the basis for a zoonosis. Transmission per se is not the major requirement for the generation of the AIDS epidemic. All HIVs do derive from simian species, but AIDS does not qualify as a zoonosis and this explanation cannot in itself account for the origin of AIDS epidemic. It is important to distinguish AIDS from true zoonoses (e.g. rabies) because research is needed to understand the processes by which animal viruses cause sustained human-to-human transmission, epidemics and even pandemics. Much is known about emerging viruses, but almost nothing is known about emerging viral diseases.

Apetrei C, Robertson DL, Marx PA. · Microbiology Division, Tulane National Primate Research Center, Covington, LA 40433, USA. · Front Biosci. · Pubmed #14766362 No free full text.

Abstract: Simian immunodeficiency virus (SIV) naturally infects non-human primates in Africa. To date, 40 SIVs have been described both in natural hosts and in heterologous species. These viruses are highly diverse and the majority cluster in 6 relatively equidistant phylogenetic lineages. At least 8 SIVs are currently considered as recombinant viruses, based on different clustering patterns in different genomic regions. Only three types of genomes are known, based on the number of accessory genes: vpr-containing genomes, vpr-vpx containing genomes and vpr-vpu-containing genomes. vpx resulted by a duplication of the vpr gene following non-homologous recombination and is characteristic of SIVs infecting the Papionini tribe of monkeys and HIV-2 in humans. vpu is characteristic of SIVcpz and HIV-1 and may have originated from a recombination involving SIVs from cercopitecini monkeys. SIV seems to be non-pathogenic in the vast majority of natural hosts in spite of a high levels of viral replication. This is probably a consequence of virus-host adaptation, in which the incubation period of the disease generally exceeds the life span of the African primate host. SIVs also have a high propensity for cross-species transmission. In the new host, the outcome may vary from inapparent infection to highly pathogenic, the former being reported for African monkeys, whereas the latter being observed in macaques and humans. The high diversity of SIVs was generated by a high mutation rate due to a low fidelity of the reverse-transcriptase and active viral and host cell turnover, host-dependent evolution and recombination. Cross-species transmission is not rare, however preferential host switching may drive the majority of cross-species transmissions. Numerous SIVs tested so far are able to grow in vitro on human PBMC, therefore it has been postulated that SIV represents a threat for infection of humans in Central Africa and that AIDS is a zoonosis. However, although the simian origin of the two HIV types is broadly acknowledged, there are no data that AIDS is acquired like a zoonosis. SIV may undergo adaptation in the new human host in order to emerge in the general population. The study of SIV in their natural hosts should provide important clues to the real threat to human populations and also elucidate the mechanisms associated with a long-term persistent viral infection without clinical consequences for the host.

Gaufin T, Gautam R, Kasheta M, Ribeiro R, Ribka E, Barnes M, Pattison M, Tatum C, MacFarland J, Montefiori D, Kaur A, Pandrea I, Apetrei C. · Division of Microbiology, Tulane National Primate Research Center, Covington, LA 70433, USA. · Blood. · Pubmed #19168789 No free full text.

Abstract: We investigated the impact of rhesus macaque (RM) B-cell depletion before inoculation with the isolate SIVsmmD215. Seven RMs were treated every 3 weeks with 50 mg/kg of an anti-CD20 antibody (rituximab) starting 7 days before inoculation for 2 (n = 4) and 5 (n = 3) months. Four control animals received no antibody. Three animals were completely depleted of CD20(+) B cells, but 4 were only partially depleted of CD20 cells in the LNs and intestine. The decrease in antibody production was consistent with the efficacy of tissue CD20 depletion. Seroconversion and neutralizing antibody production was significantly delayed in animals showing complete tissue CD20 depletion and remained at low titers in all CD20-depleted RMs. Surprisingly, there was no significant difference in acute or chronic viral loads between CD20-depleted and control animal groups. There was a tendency for lower viral set points in CD20-depleted animals. At 6 weeks after inoculation, cellular immune responses were significantly stronger in CD20-depleted animals than in controls. There was no significant difference in survival between CD20-depleted and control animals. Our data suggest that a deficiency of Ab responses did not markedly affect viral replication or disease progression and that they may be compensated by more robust cellular responses.

Souquière S, Onanga R, Makuwa M, Pandrea I, Ngari P, Rouquet P, Bourry O, Kazanji M, Apetrei C, Simon F, Roques P. · Laboratoire de Rétrovirologie, Centre International de Recherches Médicales (CIRMF), Franceville, Gabon. · J Gen Virol. · Pubmed #19141460 No free full text.

Abstract: The mandrill (Mandrillus sphinx) is naturally infected by two types of simian immunodeficiency virus (SIV): SIVmnd types 1 and 2. Both of these viruses cause long-term, non-progressive infections in their natural host despite high plasma viral loads. This study assessed the susceptibility of rhesus macaques to infection by these two types of SIVmnd and compared the virological and basic immunological characteristics of the resulting infections with those observed in natural infection in mandrills. Whilst both SIVmnd types induced similar levels of virus replication during acute infection in both mandrills and macaques, they produced a more pronounced CD4(+) T-cell depletion in rhesus macaques that persisted longer during the initial stage of infection. Pro-inflammatory cytokine responses were also induced at higher levels in rhesus macaques early in the infection. During the chronic phase of infection in mandrills, which in this case was followed for up to 2 years after infection, high levels of chronic virus replication did not induce significant changes in CD4(+) or CD8(+) T-cell counts. In rhesus macaques, the overall chronic virus replication level was lower than in mandrills. At the end of the follow-up period, although the viral loads of SIVmnd-1 and SIVmnd-2 were relatively similar in rhesus macaques, only SIVmnd-1-infected rhesus macaques showed significant CD4(+) T-cell depletion, in the context of higher levels of CD4(+) and CD8(+) T-cell activation, compared with SIVmnd-infected mandrills. The demonstration of the ability of both SIVmnd types to induce persistent infections in rhesus macaques calls for a careful assessment of the potential of these two viruses to emerge as new human pathogens.

Pandrea I, Gaufin T, Brenchley JM, Gautam R, Monjure C, Gautam A, Coleman C, Lackner AA, Ribeiro RM, Douek DC, Apetrei C. · Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433, USA. · J Immunol. · Pubmed #18981083 links to  free full text

Abstract: Chronically SIVagm-infected African green monkeys (AGMs) have a remarkably stable nonpathogenic disease course, with levels of immune activation in chronic SIVagm infection similar to those observed in uninfected monkeys and with stable viral loads for long periods of time. In vivo administration of LPS or an IL-2/diphtheria toxin fusion protein (Ontak) to chronically SIVagm-infected AGMs triggered increases in immune activation and subsequently of viral replication and depletion of intestinal CD4(+) T cells. Our study indicates that circulating microbial products can increase viral replication by inducing immune activation and increasing the number of viral target cells, thus demonstrating that immune activation and T cell proliferation are key factors in AIDS pathogenesis.

Pandrea I, Onanga R, Souquiere S, Mouinga-Ondéme A, Bourry O, Makuwa M, Rouquet P, Silvestri G, Simon F, Roques P, Apetrei C. · Departement de Virologie, Tulane National Primate Research Center, Tulane University Health Science Center, Covington, Louisiana 70433, USA. · J Virol. · Pubmed #18385229 links to  free full text

Abstract: Simian immunodeficiency virus (SIV) persistence in wild populations of African nonhuman primates (NHPs) may occur through horizontal and vertical transmission. However, the mechanism(s) and timing of the latter type of transmission have not been investigated to date. Here we present the first study of SIV transmissibility by breast-feeding in an African NHP host. Six mandrill dames were infected with plasma containing 300 50% tissue culture infective doses of SIVmnd-1 on the day after delivery. All female mandrills became infected, as demonstrated by both plasma viral loads (VLs) and anti-SIVmnd-1 seroconversion. Neither fever nor lymphadenopathy was observed. At the peak of SIVmnd-1 viral replication (days 7 to 10 postinoculation), plasma VLs were high (8 x 10(6) to 8 x 10(8) RNA copies/ml) and paralleled the high VLs in milk (4.7 x 10(4) to 5.6 x 10(5) RNA/ml). However, at the end of the breast-feeding period, after 6 months of follow-up, no sign of infection was observed for the offspring. Later on, during a 4-year follow-up examination, two of the offspring showed virological evidence of SIVmnd-1 infection. Both animals seroconverted at least 6 months after the interruption of lactation. In conclusion, despite extensive viral replication in mandrill mothers and high levels of free virus in milk, no SIVmnd-1 transmission was detectable at the time of breast-feeding or during the following months. Since we observed a markedly lower expression of CCR5 on the CD4(+) T cells of young mandrills and African green monkeys than on those of adults, we propose that low levels of this viral coreceptor on CD4(+) T cells may be involved in the lack of breast-feeding transmission in natural hosts of SIVs.

Leitner T, Dazza MC, Ekwalanga M, Apetrei C, Saragosti S. · Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA. · AIDS Res Hum Retroviruses. · Pubmed #17919106 No free full text.

Abstract: Only two of four chimpanzee subspecies (Pan troglodytes), P. troglodytes troglodytes (P.t.t.) and P. troglodytes schweinfurthii (P.t.s.), appear to carry specific simian immunodeficiency viruses (SIVs). We identified genomic features indicating that SIVcpzPtt and SIVcpzPts may have partly different evolutionary histories. A maximum likelihood test to discriminate between hypotheses of a common versus separate origin of SIVcpzPtt and SIVcpzPts revealed three putative regions of separate histories. Thus, after the P.t.t. and P.t.s. split, SIV superinfection led to further recombination resulting in the emergence of SIVcpzPts. This shows that there have been multiple SIV transfers to chimpanzees at different times in their evolution.

Pandrea IV, Gautam R, Ribeiro RM, Brenchley JM, Butler IF, Pattison M, Rasmussen T, Marx PA, Silvestri G, Lackner AA, Perelson AS, Douek DC, Veazey RS, Apetrei C. · Divisions of Comparative Pathology and Microbiology, Tulane National Primate Research Center, 18703 Three Rivers Road, Covington, LA 70433, USA. · J Immunol. · Pubmed #17709518 links to  free full text

Abstract: The predictive value of acute gut-associated lymphoid tissue (GALT) CD4+ T cell depletion in lentiviral infections was assessed by comparing three animal models illustrative of the outcomes of SIV infection: pathogenic infection (SIVsmm infection of rhesus macaques (Rh)), persistent nonprogressive infection (SIVagm infection of African green monkeys (AGM)), and transient, controlled infection (SIVagm infection of Rh). Massive acute depletion of GALT CD4+ T cells was a common feature of acute SIV infection in all three models. The outcome of this mucosal CD4+ T cell depletion, however, differed substantially between the three models: in SIVsmm-infected Rh, the acute GALT CD4+ T cell depletion was persistent and continued with disease progression; in SIVagm, intestinal CD4+ T cells were partially restored during chronic infection in the context of normal levels of apoptosis and immune activation and absence of damage to the mucosal immunologic barrier; in SIVagm-infected Rh, complete control of viral replication resulted in restoration of the mucosal barrier and immune restoration. Therefore, our data support a revised paradigm wherein severe GALT CD4+ T cell depletion during acute pathogenic HIV and SIV infections of humans and Rh is necessary but neither sufficient nor predictive of disease progression, with levels of immune activation, proliferation and apoptosis being key factors involved in determining progression to AIDS.

Gordon SN, Klatt NR, Bosinger SE, Brenchley JM, Milush JM, Engram JC, Dunham RM, Paiardini M, Klucking S, Danesh A, Strobert EA, Apetrei C, Pandrea IV, Kelvin D, Douek DC, Staprans SI, Sodora DL, Silvestri G. · Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · J Immunol. · Pubmed #17709517 links to  free full text

Abstract: HIV-infected humans and SIV-infected rhesus macaques experience a rapid and dramatic loss of mucosal CD4+ T cells that is considered to be a key determinant of AIDS pathogenesis. In this study, we show that nonpathogenic SIV infection of sooty mangabeys (SMs), a natural host species for SIV, is also associated with an early, severe, and persistent depletion of memory CD4+ T cells from the intestinal and respiratory mucosa. Importantly, the kinetics of the loss of mucosal CD4+ T cells in SMs is similar to that of SIVmac239-infected rhesus macaques. Although the nonpathogenic SIV infection of SMs induces the same pattern of mucosal target cell depletion observed during pathogenic HIV/SIV infections, the depletion in SMs occurs in the context of limited local and systemic immune activation and can be reverted if virus replication is suppressed by antiretroviral treatment. These results indicate that a profound depletion of mucosal CD4+ T cells is not sufficient per se to induce loss of mucosal immunity and disease progression during a primate lentiviral infection. We propose that, in the disease-resistant SIV-infected SMs, evolutionary adaptation to both preserve immune function with fewer mucosal CD4+ T cells and attenuate the immune activation that follows acute viral infection protect these animals from progressing to AIDS.

Apetrei C, Gautam R, Sumpter B, Carter AC, Gaufin T, Staprans SI, Else J, Barnes M, Cao R, Garg S, Milush JM, Sodora DL, Pandrea I, Silvestri G. · Division of Microbiology and Immunology, Tulane National Primate Research Center, 18703 Three Rivers Road, Covington, LA 70433, USA. · J Virol. · Pubmed #17507488 links to  free full text

Abstract: Simian immunodeficiency virus (SIV) SIV(smm) naturally infects sooty mangabeys (SMs) and is the source virus of pathogenic infections with human immunodeficiency virus type 2 (HIV-2) and SIV(mac) of humans and macaques, respectively. In previous studies we characterized SIV(smm) diversity in naturally SIV-infected SMs and identified nine different phylogenetic subtypes whose genetic distances are similar to those reported for the different HIV-1 group M subtypes. Here we report that, within the colony of SMs housed at the Yerkes National Primate Research Center, at least four SIV(smm) subtypes cocirculate, with the vast majority of animals infected with SIV(smm) subtype 1, 2, or 3, resulting in the emergence of occasional recombinant forms. While SIV(smm)-infected SMs show a typically nonpathogenic course of infection, we have observed that different SIV(smm) subtypes are in fact associated with specific immunologic features. Notably, while subtypes 1, 2, and 3 are associated with a very benign course of infection and preservation of normal CD4+ T-cell counts, three out of four SMs infected with subtype 5 show a significant depletion of CD4+ T cells. The fact that virus replication in SMs infected with subtype 5 is similar to that in SMs infected with other SIV(smm) subtypes suggests that the subtype 5-associated CD4+ T-cell depletion is unlikely to simply reflect higher levels of virus-mediated direct killing of CD4+ T-cells. Taken together, this systematic analysis of the subtype-specific features of SIV(smm) infection in natural SM hosts identifies subtype-specific differences in the pathogenicity of SIV(smm) infection.

Gautam R, Carter AC, Katz N, Butler IF, Barnes M, Hasegawa A, Ratterree M, Silvestri G, Marx PA, Hirsch VM, Pandrea I, Apetrei C. · Division of Microbiology, Tulane National Primate Research Center, Covington, LA 70433, USA. · Virology. · Pubmed #17303205 links to  free full text

Abstract: We report in vitro characterization of 11 SIVsmm strains of six lineages co-circulating in naturally infected sooty mangabeys (SMs) from US Primate Centers and showed no major differences in the in vitro replication pattern between different SIVsmm lineages. Primary SIVsmm isolates utilized CCR5 and Bonzo co-receptors in vitro. SIVsmm growth in human T cell lines was isolate-, not lineage-specific, with poor replication on Molt4-Clone8, CEMss and PM1 cells and better replication on MT2, SupT1 and CEMx174 cells. All primary SIVsmm isolates replicated on SM and human PBMCs. In vitro replication in macaques varied widely, with moderate to high replication in pig-tailed macaque PBMCs, enhanced by CD8+ T cell depletion, and highly variable replication on rhesus macaque (Rh) PBMCs. Primary SIVsmm isolates replicated in Rh monocyte-derived dendritic cells (MDDCs) and monocyte-derived macrophages (MDMs). In vivo, SIVsmm isolates replicated at high levels in all SIVsmm-infected Rh. The poor in vitro replication of primary SIVsmm isolates in Rh cells did not correlate with in vivo replication, emphasizing the value of in vivo studies.

Pandrea I, Apetrei C, Gordon S, Barbercheck J, Dufour J, Bohm R, Sumpter B, Roques P, Marx PA, Hirsch VM, Kaur A, Lackner AA, Veazey RS, Silvestri G. · Tulane National Primate Research Center, Covington, LA 70433, USA. · Blood. · Pubmed #17003371 links to  free full text

Abstract: In contrast to lentiviral infections of humans and macaques, simian immunodeficiency virus (SIV) infection of natural hosts is nonpathogenic despite high levels of viral replication. However, the mechanisms underlying this absence of disease are unknown. Here we report that natural hosts for SIV infection express remarkably low levels of CCR5 on CD4+ T cells isolated from blood, lymph nodes, and mucosal tissues. Given that this immunologic feature is found in 5 different species of natural SIV hosts (sooty mangabeys, African green monkeys, mandrills, sun-tailed monkeys, and chimpanzees) but is absent in 5 nonnatural/recent hosts (humans, rhesus, pigtail, cynomolgus macaques, and baboons), it may represent a key feature of the coevolution between the virus and its natural hosts that led to a nonpathogenic infection. Beneficial effects of low CCR5 expression on CD4+ T cells may include the reduction of target cells for viral replication and a decreased homing of activated CD4+ T cells to inflamed tissue.

Pandrea I, Silvestri G, Onanga R, Veazey RS, Marx PA, Hirsch V, Apetrei C. · Tulane National Primate Research Center, Covington, LA 70433, USA. · J Med Primatol. · Pubmed #16872282 No free full text.

Abstract: METHODS: To define potential common features of simian immunodeficiency virus (SIV) infections in different naturally infected host species, we compared the dynamics of viral replication in 31 African green monkeys (10 sabeus, 15 vervets and seven Caribbean AGMs), 14 mandrills and three sooty mangabeys (SMs) that were experimentally infected with their species-specific viruses. RESULTS: After infection, these SIVs replicated rapidly reaching viral loads (VLs) of 10(5)-10(9) copies/ml of plasma between days 9-14 post-infection (p.i). Set point viremia was established between days 42 and 60 p.i., with levels of approximately 10(5)-10(6) copies/ml in SM and mandrills, and lower levels (10(3)-10(5) copies/ml) in AGMs. VL during the chronic phase did not correlate with viral genome structure: SIVmnd-2 (a vpx-containing virus) and SIVmnd-1 (which does not contain vpu or vpx) replicated to similar levels in mandrills. VL was dependent on virus strain: vervets infected with three different viral strains showed different patterns of viral replication. The pattern of viral replication of SIVagm.sab, which uses both CCR5 and CXCR4 co-receptors was similar to those of the other viruses. CONCLUSIONS: Our results show a common pattern of SIV replication in naturally and experimentally infected hosts. This is similar overall to that observed in pathogenic SIV infection of macaques. This result indicates that differences in clinical outcome between pathogenic and non-pathogenic infections rely on host responses rather than the characteristics of the virus itself.

Pandrea I, Apetrei C, Dufour J, Dillon N, Barbercheck J, Metzger M, Jacquelin B, Bohm R, Marx PA, Barre-Sinoussi F, Hirsch VM, Müller-Trutwin MC, Lackner AA, Veazey RS. · Tulane National Primate Research Center, Covington, LA 70433, USA. · J Virol. · Pubmed #16641277 links to  free full text

Abstract: Caribbean-born African green monkeys (AGMs) were classified as Chlorocebus sabaeus by cytochrome b sequencing. Guided by these phylogenetic analyses, we developed a new model for the study of simian immunodeficiency virus (SIV) infection in natural hosts by inoculating Caribbean AGMs with their species-specific SIVagm.sab. SIVagm.sab replicated efficiently in Caribbean AGM peripheral blood mononuclear cells in vitro. During SIVagm.sab primary infection of six Caribbean AGMs, the virus replicated at high levels, with peak viral loads (VLs) of 10(7) to 10(8) copies/ml occurring by day 8 to 10 postinfection (p.i.). Set-point values of up to 2 x 10(5) copies/ml were reached by day 42 p.i. and maintained throughout follow-up (through day 450 p.i.). CD4(+) T-cell counts in the blood showed a transient depletion at the peak of VL, and then returned to near preinfection values by day 28 p.i. and remained relatively stable during the chronic infection. Preservation of CD4 T cells was also found in lymph nodes (LNs) of chronic SIVagm.sab-infected Caribbean AGMs. No activation of CD4(+) T cells was detected in the periphery in SIV-infected Caribbean AGMs. These virological and immunological profiles from peripheral blood and LNs were identical to those previously reported in African-born AGMs infected with the same viral strain (SIVagm.sab92018). Due to these similarities, we conclude that Caribbean AGMs are a useful alternative to AGMs of African origin as a model for the study of SIV infection in natural African hosts.

Onanga R, Souquière S, Makuwa M, Mouinga-Ondeme A, Simon F, Apetrei C, Roques P. · Département de Virologie, Centre International de Recherche Médicales, Gabon. · J Virol. · Pubmed #16537597 links to  free full text

Abstract: Mandrills are the only nonhuman primate (NHP) naturally infected by two types of simian immunodeficiency virus (SIV): SIVmnd-1 and SIVmnd-2. We have already reported that the high SIVmnd-1 replication during primary infection contrasts with only transient changes in CD4+ and CD8+ cell counts. Since early virus-host interactions predict viral control and disease progression in human immunodeficiency virus-infected patients, we investigated the dynamics of SIVmnd-2 primary infection in mandrills to examine the impact on immune effectors in blood and lymph nodes (LNs). To avoid in vitro strain selection, all mandrills in this study received plasma from SIVmnd-2-infected mandrills. SIVmnd-2 plasma viremia peaked at 10(7) to 10(8) RNA copies/ml between days 7 and 10. This peak was followed in all four monkeys by a decline in virus replication, with a set point level of 10(5) to 10(6) RNA copies/ml at day 42 postinfection (p.i.). Viral DNA load in PBMC and LNs also peaked between days 7 and 10 (10(5) to 10(6) DNA copies/10(6) cells) and stabilized at 10(3) to 10(4) DNA copies/10(6) cells during the chronic phase. Anti-SIVmnd-2 antibodies were detected starting from days 28 to 32. A transitory decline of CD3+ CD4+ cells in the LNs occurred in animals with high peak VLs. CD4+ and CD8+ T-cell activation in blood and LNs was noted between days 5 and 17 p.i., surrounding the peak of viral replication. This was most significant in the LNs. Activation markers then returned to preinfection values despite continuous and active viral replication during the chronic infection. The dynamics of SIVmnd-2 infection in mandrills showed a pattern similar to that of SIVmnd-1 infection. This might be a general feature of nonpathogenic SIV natural African NHP models.

Dunham R, Pagliardini P, Gordon S, Sumpter B, Engram J, Moanna A, Paiardini M, Mandl JN, Lawson B, Garg S, McClure HM, Xu YX, Ibegbu C, Easley K, Katz N, Pandrea I, Apetrei C, Sodora DL, Staprans SI, Feinberg MB, Silvestri G. · Emory University, Emory Vaccine Center, Yerkes Primate Research Center, and the School of Public Health, Atlanta, GA, USA. · Blood. · Pubmed #16522814 links to  free full text

Abstract: In contrast to human immunodeficiency virus (HIV)-infected humans, natural hosts for simian immunodeficiency virus (SIV) very rarely progress to acquired immunodeficiency syndrome (AIDS). While the mechanisms underlying this disease resistance are still poorly understood, a consistent feature of natural SIV infection is the absence of the generalized immune activation associated with HIV infection. To investigate the immunologic mechanisms underlying the absence of AIDS in SIV-infected sooty mangabeys (SMs), a natural host species, we performed a detailed analysis of the SIV-specific cellular immune responses in 110 SIV-infected SMs. We found that while SIV-specific T-cell responses are detectable in the majority of animals, their magnitude and breadth are, in fact, lower than what has been described in HIV-infected humans, both in terms of cytokine production (ie, IFN-gamma, TNF-alpha, and IL-2) and degranulation (ie, CD107a expression). Of importance, SIV-specific T-cell responses were similarly low when either SIVmac239-derived peptides or autologous SIVsmm peptides were used as stimuli. No correlation was found between SIV-specific T-cell responses and either viral load or CD4+ T-cell count, or between these responses and markers of T-cell activation and proliferation. These findings indicate that the absence of AIDS in naturally SIV-infected sooty mangabeys is independent of a strong cellular immune response to the virus.

Apetrei C, Lerche NW, Pandrea I, Gormus B, Silvestri G, Kaur A, Robertson DL, Hardcastle J, Lackner AA, Marx PA. · Division of Microbiology, Tulane National Primate Research Center, Covington, Louisiana 70433, USA. · AIDS. · Pubmed #16439864 No free full text.

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Apetrei C, Kaur A, Lerche NW, Metzger M, Pandrea I, Hardcastle J, Falkenstein S, Bohm R, Koehler J, Traina-Dorge V, Williams T, Staprans S, Plauche G, Veazey RS, McClure H, Lackner AA, Gormus B, Robertson DL, Marx PA. · Division of Microbiology and Immunology, Tulane National Primate Research Center, 18703 Three Rivers Road, Covington, LA 70433, USA. · J Virol. · Pubmed #15994793 links to  free full text

Abstract: Retrospective molecular epidemiology was performed on samples from four sooty mangabey (SM) colonies in the United States to characterize simian immunodeficiency virus SIVsm diversity in SMs and to trace virus circulation among different primate centers (PCs) over the past 30 years. The following SIVsm sequences were collected from different monkeys: 55 SIVsm isolates from the Tulane PC sampled between 1984 and 2004, 10 SIVsm isolates from the Yerkes PC sampled in 2002, 7 SIVsm isolates from the New Iberia PC sampled between 1979 and 1986, and 8 SIVsm isolates from the California PC sampled between 1975 and 1977. PCR and sequencing were done to characterize the gag, pol, and env gp36 genes. Phylogenetic analyses were correlated with the epidemiological data. Our analysis identified nine different divergent phylogenetic lineages that cocirculated in these four SM colonies in the Unites States in the past 30 years. Lineages 1 to 5 have been identified previously. Two of the newly identified SIVsm lineages found in SMs are ancestral to SIVmac251/SIVmac239/SIVmne and SIVstm. We further identified the origin of these two macaque viruses in SMs from the California National Primate Research Center. The diversity of SIVsm isolates in PCs in the United States mirrors that of human immunodeficiency virus type 1 (HIV-1) group M subtypes and offers a model for the molecular epidemiology of HIV and a new approach to vaccine testing. The cocirculation of divergent SIVsm strains in PCs resulted in founder effects, superinfections, and recombinations. This large array of SIVsm strains showing the same magnitude of diversity as HIV-1 group M subtypes should be extremely useful for modeling the efficacy of vaccination strategies under the real-world conditions of HIV-1 diversity. The genetic variability of SIVsm strains among PCs may influence the diagnosis and monitoring of SIVsm infection and, consequently, may bias the results of pathogenesis studies.

Pandrea I, Kornfeld C, Ploquin MJ, Apetrei C, Faye A, Rouquet P, Roques P, Simon F, Barré-Sinoussi F, Müller-Trutwin MC, Diop OM. · Division of Comparative Pathology, Tulane National Primate Research Center, 18703 Three Rivers Road, Covington, LA 70433, USA. · J Virol. · Pubmed #15858009 links to  free full text

Abstract: To better understand which factors govern the levels of viral loads in early lentiviral infections of primates, we developed a model that allows distinguishing between the influences of host and viral factors on viremia. Herein we report that two species of African green monkeys (Chlorocebus sabaeus and C. pygerythrus) infected with their respective wild-type simian immunodeficiency virus SIVagm viruses (SIVagm.sab92018 and SIVagm.ver644) consistently showed reproducible differences in viremia during primary infection but not at later stages of infection. Cross-infections of SIVagm.sab92018 and SIVagm.ver644 into, respectively, C. pygerythrus and C. sabaeus revealed that the dynamics of viral replication during primary infection were dependent on the viral strain used for the infection but not on the host. Hence, the kinetics of SIVagm.sab92018 and SIVagm.ver644 were similar in both sabaeus and vervet animals, indicating that the difference in viremia levels between the two groups during the early phase of infection was not associated with the host. Coreceptor usage for these two strains showed a larger coreceptor repertoire for SIVagm.sab92018, which is able to efficiently use CXCR4 in addition to CCR5, than for SIVagm.ver644, which showed a classical CCR5 coreceptor usage pattern. These differences could not be explained by different charges of the V3 loop for SIVagm.sab92018 and for SIVagm.ver644. In conclusion, our study showed that the extent of virus replication during the primary infection is primarily dependent on viral determinants.

Kornfeld C, Ploquin MJ, Pandrea I, Faye A, Onanga R, Apetrei C, Poaty-Mavoungou V, Rouquet P, Estaquier J, Mortara L, Desoutter JF, Butor C, Le Grand R, Roques P, Simon F, Barré-Sinoussi F, Diop OM, Müller-Trutwin MC. · Unité de Biologie des Rétrovirus, Institut Pasteur, Paris, France. · J Clin Invest. · Pubmed #15761496 links to  free full text

Abstract: T cell activation levels in HIV infection are predictive of AIDS progression. We searched for the immunological correlates of protection against disease progression by studying the early stages of nonpathogenic SIV infection in African green monkeys (SIVagm). The African green monkeys (AGMs) displayed high peak viremias and a transient decline in levels of blood CD4(+) and CD8(+) T cells between days 5 and 17 after infection. A concomitant increase in levels of CD4(+)DR(+), CD8(+)DR(+), and CD8(+)CD28(-) cells was detected. After the third week, T cell activation returned to baseline levels, which suggested a protective downregulation of T cell activation. A very early (24 hours after infection) and strong induction of TGF-beta1 and FoxP3 expression was detected and correlated with increases in levels of CD4(+)CD25(+) and CD8(+)CD25(+) T cells. This was followed by a significant increase in levels of IL-10, whereas IFN-gamma gene upregulation was more transient, and levels of TNF-alpha and MIP-1alpha/beta transcripts did not increase in either blood or tissues. The profiles were significantly different during primary SIV infection in macaques (SIVmac); that is, there was a delayed increase in IL-10 levels accompanied by moderate and persistent increases in TGF-beta levels. Together, our data show that SIVagm infection is associated with an immediate antiinflammatory environment and suggest that TGF-beta may participate in the generation of Tregs, which may prevent an aberrant chronic T cell hyperactivation.