Acquired Immunodeficiency Syndrome: Simon F

Brun-Vézinet F, Damond F, Simon F. · Laboratoire de virologie, Hôpital Bichat-Claude Bernard, Paris, France. · Bull Soc Pathol Exot. · Pubmed #10572662 No free full text.

Abstract: The variability of human immunodeficiency virus type 1 (HIV-1) is very high. To date, three distinct lineages of HIVs, type 1 group M, type 1 group O and type 2 are described, suggesting at least three different zoonotic infections. HIV-1 group M is responsible for the global epidemic of AIDS. At least ten subtypes of HIV-1 group M, labelled A through J, have been discovered. Viral sequences from both the gag and the env gene, particularly a part of gp 120 referred to as the V3 region have been used to identify subtypes of HIV-1 group M. The nucleotide distance between viruses of different subtypes is on average 30% for the env gene. The various subtypes are geographically distributed throughout the world. Some of the subtypes were identified as recombinant or mosaic viruses. The existence of different subtypes of HIV-1 have major implication for vaccination. They may also influence the diagnosis of HIV infection. To date, it is unclear whether subtypes of HIV-1 differ with respect to transmissibility or pathogenicity.

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.

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.

Rouet F, Ekouevi DK, Inwoley A, Chaix ML, Burgard M, Bequet L, Viho I, Leroy V, Simon F, Dabis F, Rouzioux C. · Centre de Diagnostic et de Recherches sur le SIDA, CHU de Treichville, BP V3 Abidjan, Côte d'Ivoire. · J Clin Microbiol. · Pubmed #15365003 links to  free full text

Abstract: We evaluated a two-rapid-test serial algorithm using the Determine and Genie II rapid assays, performed on-site in four peripheral laboratories during the French Agence Nationale de Recherches sur le SIDA (ANRS) 1201/1202 Ditrame Plus cohort developed for prevention of mother-to-child transmission of human immunodeficiency virus (HIV) infection in Côte d'Ivoire. A total of 1,039 specimens were retested by two commercial enzyme-linked immunosorbent assays (ELISAs). The following specimens were tested: 315 specimens found on-site to be infected with HIV type 1 (HIV-1), 8 specimens found on-site to be infected with HIV-2, 71 specimens found on-site to be infected with both HIV-1 and HIV-2, 40 specimens found on-site to have indeterminate results for HIV infection, and 605 specimens taken during a quality assurance program. For HIV discrimination, 99 positive serum samples (20 with HIV-1, 8 with HIV-2, and 71 with HIV-1 and HIV-2 on the basis of our rapid test algorithm) were retested by the Peptilav test, Western blot (WB) assays, and homemade monospecific ELISAs. Real-time DNA PCRs for the detection of HIV-1 and HIV-2 were performed with peripheral blood mononuclear cells from 35 women diagnosed on-site with HIV-1 and HIV-2 infections. Compared to the results of the ELISAs, the sensitivities of the Determine and Genie II assays were 100% (95% lower limit [95% LL], 99.1%) and 99.5% (95% confidence interval [95% CI], 98.2 to 99.9%), respectively. The specificities were 98.4% (95% CI, 96.9 to 99.3%) and 100% (95% LL, 99.3%), respectively. All serological assays gave concordant results for infections with single types. By contrast, for samples found to be infected with dual HIV types by the Genie II assay, dual reactivity was detected for only 37 samples (52.1%) by WB assays, 34 samples (47.9%) by the Peptilav assay, and 23 samples (32.4%) by the monospecific ELISAs. For specimens with dual reactivity by the Genie II assay, the rates of concordance between the real-time PCR assays and the serological assays were 25.7% for the Genie II assay, 82.9% for the Peptilav assay, 74.3% for WB assays, and 80% for the homemade ELISAs. Our algorithm provided high degrees of sensitivity and specificity comparable to those of ELISAs. Even if they are rare, women identified by the Genie II assay as being infected with HIV-1 and HIV-2 mostly appeared to be infected only with HIV-2.

Matheron S, Pueyo S, Damond F, Simon F, Leprêtre A, Campa P, Salamon R, Chêne G, Brun-Vezinet F, Anonymous00157. · Service des Maladies Infectieuses et Tropicales A, Hôpital Bichat-Claude Bernard, Assistance Publique des Hôpitaux de Paris, France. · AIDS. · Pubmed #14685053 No free full text.

Abstract: OBJECTIVES: To identify factors associated with clinical progression in HIV-2 infected patients. DESIGN: French prospective cohort initiated in 1994. METHODS: Follow-up data are collected twice a year; viral load is assessed once a year by cellular viraemia, quantitative proviral DNA and plasma RNA. A Cox proportional-hazards model was used for studying baseline factors associated with clinical progression. RESULTS: By December 2001, 217 patients had been enrolled. At inclusion, 80%, 6% and 14% were Centers for Disease Control and Prevention (CDC) group A, B and C, respectively. Median CD4 cell count was 436 x 10(6)/l. In the 48% of positive specimens, the median plasma RNA titre was 3.0 log10 copies/ml. Mean follow-up of the 179 patients seen at least twice was 34.4 months. Of these 13 died and nine progressed to group C. Ninety-three (52%) received antiretroviral therapy during a mean of 33 months, including a protease inhibitor in 48%. The probability of remaining AIDS-free was 97% and 95% at 1 and 3 years, respectively. Independent variables associated with clinical progression were age > or = 40 years [hazard ratio (HR), 11; 95% confidence interval (CI), 1.4-91.8; P = 0.03] and plasma RNA (HR, 2.5 per additional log10 copies/ml; 95% CI, 1.3-4.7, P < 0.01). Prior group B symptoms and CD4 cell count < 200 x 10(6)/l were associated with progression to AIDS. AIDS and plasma RNA were predictive of death. CONCLUSION: Considering the limited progression rate of HIV-2 infection, combined antiretroviral therapy should be discussed in patients with high plasma RNA titres, which threshold value remains to be defined. It is recommended in case of AIDS, CDC group B symptoms or CD4 cell count < 200 x 10(6)/l.

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.

Souquière S, Bibollet-Ruche F, Robertson DL, Makuwa M, Apetrei C, Onanga R, Kornfeld C, Plantier JC, Gao F, Abernethy K, White LJ, Karesh W, Telfer P, Wickings EJ, Mauclère P, Marx PA, Barré-Sinoussi F, Hahn BH, Müller-Trutwin MC, Simon F. · Laboratoire de Virologie, UGENET, SEGC, Réserve de la Lopé, Centre International de Recherches Médicales, Franceville, Gabon. · J Virol. · Pubmed #11435589 links to  free full text

Abstract: Mandrillus sphinx, a large primate living in Cameroon and Gabon and belonging to the Papionini tribe, was reported to be infected by a simian immunodeficiency virus (SIV) (SIVmndGB1) as early as 1988. Here, we have identified a second, highly divergent SIVmnd (designated SIVmnd-2). Genomic organization differs between the two viral types; SIVmnd-2 has the additional vpx gene, like other SIVs naturally infecting the Papionini tribe (SIVsm and SIVrcm) and in contrast to the other SIVmnd type (here designated SIVmnd-1), which is more closely related to SIVs infecting l'hoest (Cercopithecus lhoesti lhoesti) and sun-tailed (Cercopithecus lhoesti solatus) monkeys. Importantly, our epidemiological studies indicate a high prevalence of both types of SIVmnd; all 10 sexually mature wild-living monkeys and 3 out of 17 wild-born juveniles tested were infected. The geographic distribution of SIVmnd seems to be distinct for the two types: SIVmnd-1 viruses were exclusively identified in mandrills from central and southern Gabon, whereas SIVmnd-2 viruses were identified in monkeys from northern and western Gabon, as well as in Cameroon. SIVmnd-2 full-length sequence analysis, together with analysis of partial sequences from SIVmnd-1 and SIVmnd-2 from wild-born or wild-living mandrills, shows that the gag and pol regions of SIVmnd-2 are closest to those of SIVrcm, isolated from red-capped mangabeys (Cercocebus torquatus), while the env gene is closest to that of SIVmnd-1. pol and env sequence analyses of SIV from a related Papionini species, the drill (Mandrillus leucophaeus), shows a closer relationship of SIVdrl to SIVmnd-2 than to SIVmnd-1. Epidemiological surveys of human immunodeficiency virus revealed a case in Cameroon of a human infected by a virus serologically related to SIVmnd, raising the possibility that mandrills represent a viral reservoir for humans similar to sooty mangabeys in Western Africa and chimpanzees in Central Africa.

Ayouba A, Mauclère P, Martin PM, Cunin P, Mfoupouendoun J, Njinku B, Souquières S, Simon F. · Centre Pasteur du Cameroun, Yaoundé, Cameroon. · Emerg Infect Dis. · Pubmed #11384531 links to  free full text

Abstract: We report a survey of HIV-1 group O infection in Cameroon during 1986 to 1998. The prevalence of HIV-1/O decreased from 0.6% to 0.4%, while HIV-1/M increased from 19.2% to 31.5% from 1994 to 1998. We concluded that HIV-1/O infection is stable in Cameroon and may be declining slightly.

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.

Duval M, Faye A, Rohrlich P, Levine M, Matheron S, Larchee R, Simon F, Vilmer E. · No affiliation provided · J Acquir Immune Defic Syndr Hum Retrovirol. · Pubmed #9928741 No free full text.

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