Acquired Immunodeficiency Syndrome: Müller-Trutwin MC

Liovat AS, Jacquelin B, Ploquin MJ, Barré-Sinoussi F, Müller-Trutwin MC. · Institut Pasteur, Unité de Régulations des Infections Rétrovirales, Paris, France. · Curr HIV Res. · Pubmed #19149553 No free full text.

Abstract: African non human primates are natural hosts of SIV. The infection is generally non-pathogenic despite high steady-state levels of plasma viral RNA that in HIV-1 and SIVmac infections are associated with progression towards AIDS. The viral loads in the gut also are as high as in pathogenic HIV-1/SIVmac infections; but replication levels are lower in peripheral lymph nodes of chronically infected African green monkeys. There is a transient loss of CD4(+) T cells in the blood in SIVagm and SIVsm infections and an early dramatic and more persistent decrease in the gut. Although SIV in natural hosts is thus cytopathic, the continuous viral replication is not associated with immunopathology. T CD4(+) cells in blood, lymph nodes and gut manifest no or little increase of cell-death by apoptosis. The lymph node and gut architecture is not disrupted. The most striking difference between non-pathogenic SIV and pathogenic HIV-1/SIVmac infections is the lack of chronic T cell activation. Several studies are currently in progress to determine which factors are involved in the maintenance of the low activation level in the non-pathogenic SIV infections. There are two ways in which this could be achieved: (i) a lack of immune activation induction or (ii) an active downregulation of the immune activation. The arguments in favor of each of these two possible ways of immune activation control will be discussed in view of the most recent data in the literature. A particular focus is put on data on the innate immune system and the timing of induction of immunosuppressive mediators during the early phase of SIV infection.

Lozano Reina JM, Favre D, Kasakow Z, Mayau V, Nugeyre MT, Ka T, Faye A, Miller CJ, Scott-Algara D, McCune JM, Barré-Sinoussi F, Diop OM, Müller-Trutwin MC. · Institut Pasteur, Régulation des Infections Rétrovirales, Paris, France. · J Virol. · Pubmed #19109377 No free full text.

Abstract: Nonpathogenic simian immunodeficiency virus SIVagm infection of African green monkeys (AGMs) is characterized by the absence of a robust antibody response against Gag p27. To determine if this is accompanied by a selective loss of T-cell responses to Gag p27, we studied CD4(+) and CD8(+) T-cell responses against Gag p27 and other SIVagm antigens in the peripheral blood and lymph nodes of acutely and chronically infected AGMs. Our data show that AGMs can mount a T-cell response against Gag p27, indicating that the absence of anti-p27 antibodies is not due to the absence of Gag p27-specific T cells.

Diop OM, Ploquin MJ, Mortara L, Faye A, Jacquelin B, Kunkel D, Lebon P, Butor C, Hosmalin A, Barré-Sinoussi F, Müller-Trutwin MC. · Institut Pasteur, Dakar, Sénégal. · J Virol. · Pubmed #18385227 links to  free full text

Abstract: We addressed the role of plasmacytoid dendritic cells (PDC) in protection against AIDS in nonpathogenic simian immunodeficiency virus (SIVagm) infection in African green monkeys (AGMs). PDC were monitored in blood and lymph nodes (LNs) starting from day 1 postinfection. We observed significant declines in blood during acute infection. However, PDC then returned to normal levels, and chronically infected AGMs showed no decrease of PDC in blood. There was a significant increase of PDC in LNs during acute infection. Blood PDC displayed only weak alpha interferon (IFN-alpha) responses to TLR9 agonist stimulation before infection. However, during acute infection, both blood and LN PDC showed a transiently increased propensity for IFN-alpha production. Bioactive IFN-alpha was detected in plasma concomitant with the peak of viremia, though levels were only low to moderate in some animals. Plasma interleukin 6 (IL-6) and IL-12 were not increased. In conclusion, PDC were recruited to the LNs and displayed increased IFN-alpha production during acute infection. However, increases in IFN-alpha were transient. Together with the lack of inflammatory cytokine responses, these events might play an important role in the low level of T-cell activation which is associated with protection against AIDS in nonpathogenic SIVagm infection.

Ploquin MJ, Desoutter JF, Santos PR, Pandrea I, Diop OM, Hosmalin A, Butor C, Barre-Sinoussi F, Müller-Trutwin MC. · Unité de Régulation des Infections Rétrovirales, Institut Pasteur, Paris, France. · Retrovirology. · Pubmed #16800882 links to  free full text

Abstract: BACKGROUND: The generalized T-cell activation characterizing HIV-1 and SIVmac infections in humans and macaques (MACs) is not found in the non-pathogenic SIVagm infection in African green monkeys (AGMs). We have previously shown that TGF-beta1, Foxp3 and IL-10 are induced very early after SIVagm infection. In SIVmac-infected MACs, plasma TGF-beta1 induction persists during primary infection 1. We raised the hypothesis that MACs are unable to respond to TGF-beta1 and thus cannot resorb virus-driven inflammation. We therefore compared the very early expression dynamics of pro- and anti-inflammatory markers as well as of factors involved in the TGF-beta1 signaling pathway in SIV-infected AGMs and MACs. METHODS: Levels of transcripts encoding for pro- and anti-inflammatory markers (tnf-alpha, ifn-gamma, il-10, t-bet, gata-3) as well as for TGF-beta1 signaling mediators (smad3, smad4, smad7) were followed by real time PCR in a prospective study enrolling 6 AGMs and 6 MACs. RESULTS: During primary SIVmac infection, up-regulations of tnf-alpha, ifn-gamma and t-bet responses (days 1-16 p.i.) were stronger whereas il-10 response was delayed (4th week p.i.) compared to SIVagm infection. Up-regulation of smad7 (days 3-8 p.i.), a cellular mediator inhibiting the TGF-beta1 signaling cascade, characterized SIV-infected MACs. In AGMs, we found increases of gata-3 but not t-bet, a longer lasting up-regulation of smad4 (days 1-21 p.i), a mediator enhancing TGF-beta1 signaling, and no smad7 up-regulations. CONCLUSION: Our data suggest that the inability to resorb virus-driven inflammation and activation during the pathogenic HIV-1/SIVmac infections is associated with an unresponsiveness to TGF-beta1.

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.

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.

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.

Kirchhoff F, Schindler M, Bailer N, Renkema GH, Saksela K, Knoop V, Müller-Trutwin MC, Santiago ML, Bibollet-Ruche F, Dittmar MT, Heeney JL, Hahn BH, Münch J. · Department of Virology, Universitatsklinikum, 89081 Ulm, Germany. · J Virol. · Pubmed #15194762 links to  free full text

Abstract: The accessory Nef protein allows human immunodeficiency virus type 1 (HIV-1) to persist at high levels and to cause AIDS in infected humans. The function of HIV-1 group M subtype B nef alleles has been extensively studied, and a variety of in vitro activities believed to be important for viral pathogenesis have been established. However, the function of nef alleles derived from naturally simian immunodeficiency virus (SIV)-infected chimpanzees, the original host of HIV-1, or from the HIV-1 N and O groups resulting from independent zoonotic transmissions remains to be investigated. In the present study we demonstrate that SIVcpz and HIV-1 group N or O nef alleles down-modulate CD4, CD28, and class I or II MHC molecules and up-regulate surface expression of the invariant chain (Ii) associated with immature major histocompatibility complex (MHC) class II. Furthermore, the ability of Nef to interact with the p21-activated kinase 2 was generally conserved. The functional activity of HIV-1 group N and O nef genes did not differ significantly from group M nef alleles. However, SIVcpz nef genes as a group showed a 1.8- and 2.0-fold-higher activity in modulating CD28 (P = 0.0002) and Ii (P = 0.016) surface expression, respectively, but were 1.7-fold less active in down-regulating MHC class II molecules (P = 0.006) compared to HIV-1 M nef genes. Our finding that primary SIVcpz nef alleles derived from naturally infected chimpanzees modulate the surface expression of various human cellular receptors involved in T-cell activation and antigen presentation suggests that functional nef genes helped the chimpanzee virus to persist efficiently in infected humans immediately after zoonotic transmission.

Gueye A, Diop OM, Ploquin MJ, Kornfeld C, Faye A, Cumont MC, Hurtrel B, Barré-Sinoussi F, Müller-Trutwin MC. · Unité de Biologie des Rétrovirus, Institut Pasteur, Paris, France. · J Med Primatol. · Pubmed #15061721 No free full text.

Abstract: African green monkeys (AGMs) persistently infected with SIVagm do not develop AIDS, although their plasma viremia levels can reach those reported for pathogenic HIV-1 and SIVmac infections. In contrast, the viral burden in lymph nodes in SIVagm-infected AGMs is generally lower in comparison with HIV/SIVmac pathogenic infections, at least during the chronic phase of SIVagm infection. We searched for the primary targets of viral replication, which might account for the high viremias in SIVagm-infected AGMs. We evaluated for the first time during primary infection SIVagm dissemination in various lymphoid and non-lymphoid tissues. Sixteen distinct organs at a time point corresponding to maximal virus production were analyzed for viral RNA and DNA load. At days 8 and 9 p.i., viral RNA could be detected in a wide range of tissues, such as jejunum, spleen, mesenteric lymph nodes, thymus and lung. Quantification of viral DNA and RNA as well as of productively infected cells revealed that viral replication during this early phase takes place mainly in secondary lymphoid organs and in the gut (5 x 10(4)-5 x 10(8) RNA copies/10(6) cells). By 4 years p.i., RNA copy numbers were below detection level in thymus and lung. Secondary lymphoid organs displayed 6 x 10(2)-2 x 10(6) RNA copies/10(6) cells, while some tissue fragments of ileum and jejunum still showed high viral loads (up to 10(9) copies/10(6) cells). Altogether, these results indicate a rapid dissemination of SIVagm into lymphoid tissues, including the small intestine. The latter, despite showing marked regional variations, most likely contributes significantly to the high levels of viremia observed during SIVagm infection.

Ploquin MJ, Diop OM, Sol-Foulon N, Mortara L, Faye A, Soares MA, Nerrienet E, Le Grand R, Van Kooyk Y, Amara A, Schwartz O, Barré-Sinoussi F, Müller-Trutwin MC. · Unité de Biologie des Rétrovirus, Institut Pasteur, Paris, France. · J Virol. · Pubmed #14694112 links to  free full text

Abstract: African green monkeys (AGMs) infected by simian immunodeficiency virus (SIV) SIVagm are resistant to AIDS. SIVagm-infected AGMs exhibit levels of viremia similar to those described during pathogenic human immunodeficiency virus type 1 (HIV-1) and SIVmac infections in humans and macaques, respectively, but contain lower viral loads in their lymph nodes. We addressed the potential role of dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN; CD209) in viral dissemination. In previous studies, it has been shown that human DC-SIGN and macaque DC-SIGN allow transmission of HIV and SIVmac to T cells. Here, we looked at the ability of DC-SIGN derived from AGM lymph nodes to interact with SIVagm. We show that DC-SIGN-expressing cells are present mainly in the medulla and often within the cortex and/or paracortex of AGM lymph nodes. We describe the isolation and characterization of at least three isoforms of dc-sign mRNA in lymph nodes of AGMs. The predicted amino acid sequence from the predominant mRNA isoform, DC-SIGNagm1, is 92 and 99% identical to the corresponding human and rhesus macaque DC-SIGN amino acid sequences, respectively. DC-SIGNagm1 is characterized by the lack of the fourth motif in the repeat domain. This deletion was also detected in the dc-sign gene derived from thirteen animals belonging to five other African monkey species and from four macaques (Macaca fascicularis and M. mulatta). Despite three- to seven-amino-acid modifications compared to DC-SIGNmac, DC-SIGNagm1 allows transmission of SIVagm to T cells. Furthermore, AGM monocyte-derived dendritic cells (MDDC) expressed at least 100,000 DC-SIGN molecules and were able to transmit SIVagm to T cells. At a low multiplicity of infection (10(-5) 50% tissue culture infective doses/cell), viral transmission by AGM MDDC was mainly DC-SIGN dependent. The present study reveals that DC-SIGN from a natural host species of SIV has the ability to act as an efficient attachment and transmission factor for SIVagm and suggests the absence of a direct link between this ability and viral load levels in lymph nodes.

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.

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.

Diop OM, Gueye A, Dias-Tavares M, Kornfeld C, Faye A, Ave P, Huerre M, Corbet S, Barre-Sinoussi F, Müller-Trutwin MC. · Laboratoire de Rétrovirologie, Institut Pasteur, Dakar, Senegal. · J Virol. · Pubmed #10906207 links to  free full text

Abstract: In contrast to pathogenic human immunodeficiency virus and simian immunodeficiency virus (SIV) infections, chronic SIVagm infections in African green monkeys (AGMs) are characterized by persistently low peripheral and tissue viral loads that correlate with the lack of disease observed in these animals. We report here data on the dynamics of acute SIVagm infection in AGMs that exhibit remarkable similarities with viral replication patterns observed in peripheral blood during the first 2 weeks of pathogenic SIVmac infections. Plasma viremia was evident at day 3 postinfection (p.i.) in AGMs, and rapid viral replication led by days 7 to 10 to peak viremias characterized by high levels of antigenemia (1.2 to 5 ng of p27/ml of plasma), peripheral DNA viral load (10(4) to 10(5) DNA copies/10(6) peripheral blood mononuclear cells [PBMC]), and plasma RNA viral load (2 x 10(6) to 2 x 10(8) RNA copies/ml). The lymph node (LN) RNA and DNA viral load patterns were similar to those in blood, with peaks observed between day 7 and day 14. These values in LNs (ranging from 3 x 10(5) to 3 x 10(6) RNA copies/10(6) LN cell [LNC] and 10(3) to 10(4) DNA copies/10(6) LNC) were at no time point higher than those observed in the blood. Both in LNs and in blood, rapid and significant decreases were observed in all infected animals after this peak of viral replication. Within 3 to 4 weeks p. i., antigenemia was no longer detectable and peripheral viral loads decreased to values similar to those characteristic of the chronic phase of infection (10(2) to 10(3) DNA copies/10(6) PBMC and 2 x 10(3) to 2 x 10(5) RNA copies/ml of plasma). In LNs, viral loads declined to 5 x 10(1) to 10(3) DNA copies and 10(4) to 3 x 10(5) RNA copies per 10(6) LNC at day 28 p.i. and continued to decrease until day 84 p.i. (<10 to 3 x 10(4) RNA copies/10(6) LNC). Despite extensive viremia during primary infection, neither follicular hyperplasia nor CD8(+) cell infiltration into LN germinal centers was detected. Altogether, these results indicate that the nonpathogenic outcome of SIVagm infection in its natural host is associated with a rapidly induced control of viral replication in response to SIVagm infection, rather than with a poorly replicating virus or a constitutive host genetic resistance to virus replication.

Müller-Trutwin MC, Corbet S, Hansen J, Georges-Courbot MC, Diop O, Rigoulet J, Barré-Sinoussi F, Fomsgaard A. · Unité de Biologie des Rétrovirus, Institut Pasteur, Paris, France. · AIDS Res Hum Retroviruses. · Pubmed #10408730 No free full text.

Abstract: African monkeys can be naturally infected with SIV but do not progress to AIDS. Since mutations in the human CCR5 gene have been shown to influence susceptibility to HIV infection and disease progression, we have now investigated whether mutations in CCR5-coding sequences in African nonhuman primates can explain species-specific differences in susceptibility to lentiviral infection. The animals studied comprise chronically infected monkeys corresponding to four natural hosts of SIV (Cercopithecus aethiops, Cercopithecus pygerythrus, Cercopithecus sabaeus, and Cercopithecus tantalus), noninfected animals from three species that are known to be susceptible to SIV infection (Cercopithecus patas, Cercopithecus Ihoesti, and Pan troglodytes), and monkeys of six species that do not carry SIV in the wild (Cercocebus galeritus, Cercocebus aterrimus, Cercopithecus ascanius, Cercopithecus nictitans, Cercopithecus neglectus, and Cercopithecus cephus). We observed a high degree of genetic divergence among the species. The rate of accumulation of amino acid mutations was, however, not higher in SIV carriers than in other nonhuman primates. No homozygous premature stop codons, deletions, or frameshift mutations were detected. In at least two animals, one infected AGM (Cercopithecus tantalus) and one noninfected monkey (Cercocebus aterrimus), the CCR5 alleles identified encode functional proteins, as they were identical in terms of amino acid sequence to that of functional CCR5 reported in the literature. We found no other consistent differences in the genetic variability of CCR5-coding sequences between the nonhuman primates that are carriers of SIV and those that are not.

Menu E, Reynes JM, Müller-Trutwin MC, Guillemot L, Versmisse P, Chiron M, An S, Trouplin V, Charneau P, Fleury H, Barré-Sinoussi F, Sainte Marie FF. · Institut Pasteur, Unité de Biologie des Rétrovirus, Paris, France. · J Acquir Immune Defic Syndr Hum Retrovirol. · Pubmed #10225231 No free full text.

Abstract: To investigate the genetic and biologic features of HIV-1 strains circulating in Cambodia, viruses from 95 HIV-1-seropositive individuals were subtyped by heteroduplex mobility assay (HMA) and 23 were further analyzed for their biologic characteristics. Eighty-nine individuals were clearly infected by HIV-1 subtype E. The other six samples were sequenced, together with 17 HMA subtype E samples. All but one of the 23 Cambodian env sequences clustered with previously described Thai and Vietnamese subtype E sequences, bearing a GPGQ motif at the tip of the V3 loop; the last had a GPGR motif and was phylogenetically equidistant from Asian and African subtype E viruses. Nonsyncytium-inducing, CCR5-dependent viruses predominated in patients of clinical stage B even in some with a high viral load and were detected in about 50% of the patients of stage C. All syncytium-inducing strains, mostly from AIDS patients, used both CCR5 and CXCR4. The presence of syncytium-inducing viruses did not correlate with the plasma viral load. These data show that CCR5-dependent HIV-1 subtype E is currently predominant in Cambodia. The analysis of clinical and virologic markers strongly supports the idea that dynamics of the viral population during subtype E infection in Southeast Asia is similar to that of subtype B infection in Europe and the United States.