Acquired Immunodeficiency Syndrome: Roques P

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, 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.

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.

Schindler M, Münch J, Kutsch O, Li H, Santiago ML, Bibollet-Ruche F, Müller-Trutwin MC, Novembre FJ, Peeters M, Courgnaud V, Bailes E, Roques P, Sodora DL, Silvestri G, Sharp PM, Hahn BH, Kirchhoff F. · Department of Virology, University of Ulm, 89081 Ulm, Germany. · Cell. · Pubmed #16777597 No free full text.

Abstract: High-level immune activation and T cell apoptosis represent a hallmark of HIV-1 infection that is absent from nonpathogenic SIV infections in natural primate hosts. The mechanisms causing these varying levels of immune activation are not understood. Here, we report that nef alleles from the great majority of primate lentiviruses, including HIV-2, downmodulate TCR-CD3 from infected T cells, thereby blocking their responsiveness to activation. In contrast, nef alleles from HIV-1 and a subset of closely related SIVs fail to downregulate TCR-CD3 and to inhibit cell death. Thus, Nef-mediated suppression of T cell activation is a fundamental property of primate lentiviruses that likely evolved to maintain viral persistence in the context of an intact host immune system. This function was lost during viral evolution in a lineage that gave rise to HIV-1 and may have predisposed the simian precursor of HIV-1 for greater pathogenicity in humans.

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.

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.

Pandrea I, Onanga R, Kornfeld C, Rouquet P, Bourry O, Clifford S, Telfer PT, Abernethy K, White LT, Ngari P, Müller-Trutwin M, Roques P, Marx PA, Simon F, Apetrei C. · Laboratoire de Virologie, UGENET, SEGC, Réserve de la Lopé, Centre de Primatologie, Centre International de Recherches Médicales, BP769, Franceville, Gabon, France. · Virology. · Pubmed #14675630 No free full text.

Abstract: Viral loads were investigated in SIVmnd-1 chronically infected mandrills and the results were compared with those previously observed in other nonpathogenic natural SIV infections. Four naturally and 11 experimentally SIVmnd-1-infected mandrills from a semi-free-ranging colony were studied during the chronic phase of infection. Four SIVmnd-1-infected wild mandrills were also included for comparison. Twelve uninfected mandrills were used as controls. Viral loads in all chronically infected mandrills ranged from 10(5) to 9 x 10(5) copies/ml and antibody titers ranged from 200 to 14,400 and 200 to 12,800 for anti-V3 and anti-gp36, respectively. There were no differences between groups of wild and captive mandrills. Both parameters were stable during the follow-up, and no clinical signs of immune suppression were observed. Chronic SIVmnd-1-infected mandrills presented slight increases in CD20+ and CD28+/CD8+ cell counts, and a slight decrease in CD4+/CD3+ cell counts. A slight CD4+/CD3+ cell depletion was also observed in old uninfected controls. Similar to other nonpathogenic models of lentiviral infection, these results show a persistent high level of SIVmnd-1 replication during chronic infection of mandrills, with minimal effects on T cell subpopulations.

Onanga R, Kornfeld C, Pandrea I, Estaquier J, Souquière S, Rouquet P, Mavoungou VP, Bourry O, M'Boup S, Barré-Sinoussi F, Simon F, Apetrei C, Roques P, Müller-Trutwin MC. · Département de Virologie, Centre de Primatologie, Centre International de Recherches Médicales, Franceville BP 769, Gabon. · J Virol. · Pubmed #12239301 links to  free full text

Abstract: Early events during human immunodeficiency virus infections are considered to reflect the capacity of the host to control infection. We have studied early virus and host parameters during the early phase of simian immunodeficiency virus SIVmnd-1 nonpathogenic infection in its natural host, Mandrillus sphinx. Four mandrills were experimentally infected with a primary SIVmnd-1 strain derived from a naturally infected mandrill. Two noninfected control animals were monitored in parallel. Blood and lymph nodes were collected at three time points before infection, twice a week during the first month, and at days 60, 180, and 360 postinfection (p.i.). Anti-SIVmnd-1 antibodies were detected starting from days 28 to 32 p.i. Neither elevated temperature nor increased lymph node size were observed. The viral load in plasma peaked between days 7 to 10 p.i. (2 x 10(6) to 2 x 10(8) RNA equivalents/ml). Viremia then decreased 10- to 1,000-fold, reaching the viral set point between days 30 to 60 p.i. The levels during the chronic phase of infection were similar to that in the naturally infected donor mandrill (2 x 10(5) RNA equivalents/ml). The CD4(+) cell numbers and percentages in blood and lymph nodes decreased slightly (<10%) during primary infection, and CD8(+) cell numbers increased transiently. All values returned to preinfection infection levels by day 30 p.i. CD8(+) cell numbers or percentages, in peripheral blood and lymph nodes, did not increase during the 1 year of follow-up. In conclusion, SIVmnd-1 has the capacity for rapid and extensive replication in mandrills. Despite high levels of viremia, CD4(+) and CD8(+) cell numbers remained stable in the post-acute phase of infection, raising questions regarding the susceptibility of mandrill T cells to activation and/or cell death in response to SIVmnd-1 infection in vivo.

Müller-Trutwin MC, Corbet S, Souquière S, Roques P, Versmisse P, Ayouba A, Delarue S, Nerrienet E, Lewis J, Martin P, Simon F, Barré-Sinoussi F, Mauclère P. · Unité de Biologie des Rétrovirus, Institut Pasteur, Paris, France. · J Med Primatol. · Pubmed #11085579 No free full text.

Abstract: Thus far, simian immunodeficiency virus from chimpanzees (SIVcpz) genomes have been characterized as Pan troglodytes troglodytes and show a strong relation with human immunodeficiency virus (HIV)-1 N in their env genes. We fully characterized another SIVcpz from P. t. troglodytes. This chimpanzee (Cam5) was, as was also the host of SIVcpz-cam3, wild born in Cameroon, a region where all three groups of HIV-1 (M, N and O) co-occur. In contrast to other SIVcpz, SIVcpz-cam5 was isolated immediately after the rescue of the animal. Our data demonstrate that SIVcpz-cam5, like SIVcpz-cam3, grows easily on human peripheral blood mononuclear cells (PBMCs) and uses CCR5 as a co-receptor similar to HIV-1 N YBF30. Phylogenetic analysis based on the entire env gene shows that SIVcpz-cam5 falls into the same unique subcluster as HIV-1 N YBF30, SIVcpz-cam3 and SIVcpz-US. A phylogenetic relationship was also found with the vif gene of HIV-1 N. This study provides proof that HIV-1 N related viruses circulate in wild P. t. troglodytes.

Mognetti B, Moussa M, Croitoru J, Menu E, Dormont D, Roques P, Chaouat G. · Laboratoire de Biologie de la Relation Materno-foetale, Inserm U131, Hôpital A. Béclère, Clamart, France. · Clin Exp Immunol. · Pubmed #10691921 links to  free full text

Abstract: We examined CD4 and major HIV-1 co-receptor expression by trophoblast cells (TC) from early placentas, and the permissiveness of TC for infection by several natural HIV-1 isolates in vitro. Ten early placentas (4-6 weeks of gestation) from HIV- women were obtained after elective abortion. CD4 and HIV-1 co-receptor expression by TC was examined in terms of both mRNA and protein. The same TC were then challenged with three clinical HIV isolates of known phenotype, two originating from mothers who transmitted the virus to their child and one from a vertically infected newborn. TC infection was detected by polymerase chain reaction. CD4 expression was detected in five of the 10 placentas, while membrane protein expression of CCR3, CXCR4 and CCR5 was detected in every case, despite quantitative differences among individuals. Bonzo, GPR1 and ChemR23 mRNAs were detected in all TC preparations. TC from seven out of eight placentas were permissive to HIV entry, but no productive viral replication was detected (reverse transcriptase activity in culture supernatants). Interestingly, the addition of chemokine(s) or a CD4-blocking antibody to the cultures failed to inhibit TC virus entry. These data point to marked interindividual variability in HIV co-receptor expression by trophoblast cells and show that TC from early placentas can be infected in vitro by clinical HIV-1 isolates. They also suggest that viral entry in vitro might occur through a mechanism independent of both CD4 and chemokine receptors.

Pandrea I, Onanga R, Rouquet P, Bourry O, Ngari P, Wickings EJ, Roques P, Apetrei C. · No affiliation provided · AIDS. · Pubmed #11826852 No free full text.

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