Acquired Immunodeficiency Syndrome: Silvestri G

Sodora DL, Silvestri G. · No affiliation provided · AIDS. · Pubmed #18301056 No free full text.

This publication has no abstract.

Silvestri G. · Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · J Med Primatol. · Pubmed #19187426 No free full text.

Abstract: Despite many years of intense scientific effort, the pathogenic mechanisms underlying the immunodeficiency that follows human immunodeficiency virus (HIV) infection are still poorly understood. This lack of understanding is likely the main reason why at present there is neither a cure nor a vaccine for AIDS. Important clues on the immunopathogenesis of primate lentiviral infections have been provided by comparative studies of two simian models of SIV infection: the non-pathogenic SIV infection of sooty mangabey, an African natural host species, and the pathogenic SIV-infection of non-natural host rhesus macaques, that develop a disease that closely resembles AIDS in humans. While the final mechanisms underlying the difference in infection outcome between these two species are still incompletely understood, a series of recent studies has allowed the identification of key similarities and differences between the two models of infection. In this article we summarize these findings and review the main implications in terms of HIV pathogenesis, therapy, and vaccines.

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.

Silvestri G. · Department of Pathology, Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · J Intern Med. · Pubmed #19093963 No free full text.

Abstract: In stark contrast to human immunodeficiency virus (HIV)-infected individuals who, if left untreated, almost invariably progress to acquired immunodeficiency syndrome (AIDS), natural hosts for the simian immunodeficiency viruses (SIV) remain asymptomatic throughout the course of infection. This observation represents one of the main unresolved puzzles of AIDS research, particularly if one considers that natural SIV infections are characterized by chronically high levels of viraemia as well as intrinsic virus cytopathicity comparable with that of HIV. In this review, I discuss the basic immunological features of natural, nonpathogenic SIV infections, the evidence suggesting that attenuated, rather than extraordinarily strong, immune responses to the virus may favour their benign course, and the implications of these findings in terms of HIV therapy and vaccines.

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.

Silvestri G, Paiardini M, Pandrea I, Lederman MM, Sodora DL. · Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. · J Clin Invest. · Pubmed #17975656 links to  free full text

Abstract: In striking contrast to HIV infection, natural SIV infection of African nonhuman primates is asymptomatic and usually does not induce significant CD4+ T cell depletion despite high levels of virus replication. Recently, significant progress has been made in understanding the mechanisms underlying the remarkable difference in infection outcome between natural and nonnatural HIV/SIV hosts. These advances include the identification of limited immune activation as a key factor protecting natural SIV hosts from AIDS and the discovery of low CC chemokine receptor 5 expression on CD4+ T cells as a specific and consistent immunologic feature in these animals. Further elucidation of the pathways by which the differences in immune activation between natural and nonnatural hosts are manifest holds promise for the design of novel therapeutic approaches to HIV infection.

Silvestri G. · Department of Medicine and Microbiology and Immunology; Emory Vaccine Center, Emory University School of Medicine; Atlanta, GA 30329, USA. · J Med Primatol. · Pubmed #16128919 No free full text.

Abstract: Simian immunodeficiency viruses (SIV) infection of sooty mangabey (SM) monkeys (Cercocebus atys), a natural host species, does not induce CD4+ T cell depletion and acquired immunodeficiency syndrome (AIDS) despite chronic high levels of virus replication. In contrast, SIV infection of non-natural host species, such as rhesus macaques (RM), induces a disease that closely resembles AIDS in humans. The mechanisms underlying the lack of disease progression in SIV-infected SMs are incompletely understood, but certainly reflect a complex evolutionary adaptation whereby the host immune system is not significantly damaged by the highly replicating virus. It is now widely recognized that a better understanding of these mechanisms may provide clues to the pathogenesis of immunodeficiency in HIV-infected humans. In this article I discuss five different hypotheses that may account for the non-pathogenic course of infection in SIV-infected SMs and briefly review the available data supporting each of these hypotheses.

Moanna A, Dunham R, Paiardini M, Silvestri G. · Emory Vaccine Center, Emory University School of Medicine, 954 Gatewood Road NE, Atlanta, GA 30329, USA. · Curr HIV/AIDS Rep. · Pubmed #16091244 No free full text.

Abstract: Recent studies have emphasized the role of a chronic, generalized activation of the immune system as a prominent cause of CD4+ T-cell depletion in HIV-infected patients. The HIV-induced immune activation is a strong predictor of disease progression in humans, and lack of immune activation is a key feature of nonpathogenic simian immunodeficiency virus (SIV) infection of natural hosts. The mechanisms by which immune activation induces CD4+ T-cell depletion are still incompletely understood, but likely involve changes in the complex dynamics of the naive, memory, and effector subsets of T cells. A better understanding of how HIV-induced immune activation leads to CD4+ T-cell depletion may provide new targets for immune-based interventions that could be used, in addition to standard antiretroviral therapy, to slow disease progression in HIV-infected individuals.

Hurtrel B, Petit F, Arnoult D, Müller-Trutwin M, Silvestri G, Estaquier J. · Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, Paris, cedex 15, France. · Cell Death Differ. · Pubmed #15818408 links to  free full text

Abstract: Pathogenic human immunodeficiency virus (HIV)/Simian immunodeficiency virus (SIV) infection is associated with increased T-cell apoptosis. In marked contrast to HIV infection in humans and SIV infection in macaques, the SIV infection of natural host species is typically nonpathogenic despite high levels of viral replication. In these nonpathogenic primate models, no observation of T-cell apoptosis was observed, suggesting that either SIV is less capable of directly inducing apoptosis in natural hosts (likely as a result of coevolution/coadaptation with the host) or, alternatively, that the indirect T-cell apoptosis plays the key role in determining the HIV-associated T-cell depletion and progression to acquired immune deficiency syndrome (AIDS). Understanding the molecular and cellular mechanisms responsible for the disease-free equilibrium in natural hosts for SIV infection, including those determining the absence of high levels of T-cell apoptosis, is likely to provide important clues regarding the mechanisms of AIDS pathogenesis in humans.

Garber DA, Silvestri G, Feinberg MB. · Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA. · Lancet Infect Dis. · Pubmed #15219551 No free full text.

Abstract: The unremitting devastation created by the AIDS pandemic will probably only be controlled when a vaccine is developed that is safe, effective, affordable, and simple enough to permit implementation in developing countries where the impact of AIDS is most severe. Although formidable practical, political, economic, social, and ethical challenges face the AIDS vaccine development effort, the most fundamental challenges now reside at the level of the basic biology of HIV-1 infection and pathogenesis. Of these biological considerations, three questions loom especially large: can we design immunogens that will elicit neutralising antibodies that are reactive against a wide variety of primary HIV isolates; will vaccine-elicited cytotoxic T cells be fundamentally better at controlling HIV-1 replication and ameliorating disease progression than those responses that arise during natural HIV infection; and to what extent will the tremendous global genetic diversity of HIV-1 compromise the breadth of vaccine-elicited protective immunity and the overall effectiveness of an AIDS vaccine? Although these are three exceptionally challenging questions, they are now being approached with clear hypotheses whose testing is being facilitated by an ever-improving array of technologies for vaccine design and immunological characterisation. The extent to which the field of AIDS vaccine research can now come together to answer these questions in the best coordinated, most efficient manner will probably be an important determinant of how and when an effective AIDS vaccine will be developed.

Paiardini M, Cervasi B, Dunham R, Sumpter B, Radziewicz H, Silvestri G. · Division of Infectious Diseases, Department of Medicine, Emory Vaccine Center, Emory University School of Medicine, 954 Gatewood Road NE, Atlanta, GA 30329, USA. · Immunol Res. · Pubmed #15181287 No free full text.

Abstract: For a number of years the pathogenesis of AIDS was thought to be essentially related to direct human immunodeficiency virus (HIV)-mediated killing of CD4+ T cells. More recently, attention has shifted to pathogenic models that emphasize the role of generalized immune system activation and the excess apoptosis of uninfected T cells in inducing HIV-associated CD4+ T-cell depletion. The main focus of our research is to better define the determinants and the consequences of these "indirect" mechanisms of immunodeficiency by studying both HIV-infected patients and nonhuman primates infected with simian immunodeficiency virus (SIV). We have discovered that pathogenic models of retroviral infections of primates (i.e., HIV infection in humans and SIV infection in rhesus macaques) are associated with the presence of a set of perturbations of normal cell-cycle control in T lymphocytes. These perturbations, to which we collectively refer to as cell-cycle dysregulation, or CCD, may represent an important biological link between chronic immune activation and excess apoptosis and therefore may play a significant role in the pathogenesis of AIDS. A better understanding of the determinants and consequences of CCD may pave the way for the introduction of new therapeutic strategies to be used in addition to standard antiretroviral therapy in HIV-infected patients.

Keele BF, Jones JH, Terio KA, Estes JD, Rudicell RS, Wilson ML, Li Y, Learn GH, Beasley TM, Schumacher-Stankey J, Wroblewski E, Mosser A, Raphael J, Kamenya S, Lonsdorf EV, Travis DA, Mlengeya T, Kinsel MJ, Else JG, Silvestri G, Goodall J, Sharp PM, Shaw GM, Pusey AE, Hahn BH. · Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. · Nature. · Pubmed #19626114 No free full text.

Abstract: African primates are naturally infected with over 40 different simian immunodeficiency viruses (SIVs), two of which have crossed the species barrier and generated human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2). Unlike the human viruses, however, SIVs do not generally cause acquired immunodeficiency syndrome (AIDS) in their natural hosts. Here we show that SIVcpz, the immediate precursor of HIV-1, is pathogenic in free-ranging chimpanzees. By following 94 members of two habituated chimpanzee communities in Gombe National Park, Tanzania, for over 9 years, we found a 10- to 16-fold higher age-corrected death hazard for SIVcpz-infected (n = 17) compared to uninfected (n = 77) chimpanzees. We also found that SIVcpz-infected females were less likely to give birth and had a higher infant mortality rate than uninfected females. Immunohistochemistry and in situ hybridization of post-mortem spleen and lymph node samples from three infected and two uninfected chimpanzees revealed significant CD4(+) T-cell depletion in all infected individuals, with evidence of high viral replication and extensive follicular dendritic cell virus trapping in one of them. One female, who died within 3 years of acquiring SIVcpz, had histopathological findings consistent with end-stage AIDS. These results indicate that SIVcpz, like HIV-1, is associated with progressive CD4(+) T-cell loss, lymphatic tissue destruction and premature death. These findings challenge the prevailing view that all natural SIV infections are non-pathogenic and suggest that SIVcpz has a substantial negative impact on the health, reproduction and lifespan of chimpanzees in the wild.

Gornalusse G, Mummidi S, He W, Silvestri G, Bamshad M, Ahuja SK. · Department of Medicine, Veterans Administration Research Center for AIDS and HIV-1 Infection, South Texas Veterans Health Care System, University of Texas Health Science Center, San Antonio, Texas, United States of America. · PLoS Genet. · Pubmed #19180232 links to  free full text

This publication has no abstract.

Velu V, Titanji K, Zhu B, Husain S, Pladevega A, Lai L, Vanderford TH, Chennareddi L, Silvestri G, Freeman GJ, Ahmed R, Amara RR. · Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA. · Nature. · Pubmed #19078956 No free full text.

Abstract: Chronic immunodeficiency virus infections are characterized by dysfunctional cellular and humoral antiviral immune responses. As such, immune modulatory therapies that enhance and/or restore the function of virus-specific immunity may protect from disease progression. Here we investigate the safety and immune restoration potential of blockade of the co-inhibitory receptor programmed death 1 (PD-1) during chronic simian immunodeficiency virus (SIV) infection in macaques. We demonstrate that PD-1 blockade using an antibody to PD-1 is well tolerated and results in rapid expansion of virus-specific CD8 T cells with improved functional quality. This enhanced T-cell immunity was seen in the blood and also in the gut, a major reservoir of SIV infection. PD-1 blockade also resulted in proliferation of memory B cells and increases in SIV envelope-specific antibody. These improved immune responses were associated with significant reductions in plasma viral load and also prolonged the survival of SIV-infected macaques. Blockade was effective during the early (week 10) as well as late ( approximately week 90) phases of chronic infection even under conditions of severe lymphopenia. These results demonstrate enhancement of both cellular and humoral immune responses during a pathogenic immunodeficiency virus infection by blocking a single inhibitory pathway and identify a novel therapeutic approach for control of human immunodeficiency virus infections.

Paiardini M, Cervasi B, Engram JC, Gordon SN, Klatt NR, Muthukumar A, Else J, Mittler RS, Staprans SI, Sodora DL, Silvestri G. · Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia 19143, USA. · Blood. · Pubmed #18832134 No free full text.

Abstract: Bone marrow (BM) is the key hematopoietic organ in mammals and is involved in the homeostatic proliferation of memory CD8(+) T cells. Here we expanded on our previous observation that BM is a preferential site for T-cell proliferation in simian immunodeficiency virus (SIV)-infected sooty mangabeys (SMs) that do not progress to AIDS despite high viremia. We found high levels of mature T-cell proliferation, involving both naive and memory cells, in healthy SMs and rhesus macaques (RMs). In addition, we observed in both species that lineage-specific, BM-based T-cell proliferation follows antibody-mediated in vivo CD4(+) or CD8(+) T-cell depletion, thus indicating a role for the BM in maintaining T-cell homeostasis under depleting circumstances. We also observed that, in SIV-infected SMs, but not RMs, the level of proliferation of BM-based CD4(+) T cells is higher than that of circulating CD4(+) T cells. Interestingly, limited BM-based CD4(+) T-cell proliferation was found in SIV-infected SMs with low CD4(+) T-cell counts, suggesting a regenerative failure in these animals. Collectively, these results indicate that BM is involved in maintaining T-cell homeostasis in primates and suggest a role for BM-based CD4(+) T-cell proliferation in determining the benign nature of natural SIV infection of SMs.

Muthumani K, Choo AY, Shedlock DJ, Laddy DJ, Sundaram SG, Hirao L, Wu L, Thieu KP, Chung CW, Lankaraman KM, Tebas P, Silvestri G, Weiner DB. · Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · J Virol. · Pubmed #18799583 links to  free full text

Abstract: Chronic viral infection is characterized by the functional impairment of virus-specific T-cell responses. Recent evidence has suggested that the inhibitory receptor programmed death 1 (PD-1) is specifically upregulated on antigen-specific T cells during various chronic viral infections. Indeed, it has been reported that human immunodeficiency virus (HIV)-specific T cells express elevated levels of PD-1 and that this expression correlates with the viral load and inversely with CD4(+) T-cell counts. More importantly, antibody blockade of the PD-1/PD-L1 pathway was sufficient to both increase and stimulate virus-specific T-cell proliferation and cytokine production. However, the mechanisms that mediate HIV-induced PD-1 upregulation are not known. Here, we provide evidence that the HIV type 1 (HIV-1) accessory protein Nef can transcriptionally induce the expression of PD-1 during infection in vitro. Nef-induced PD-1 upregulation requires its proline-rich motif and the activation of the downstream kinase p38. Further, inhibition of Nef activity by p38 MAPK inhibitor effectively blocked PD-1 upregulation, suggesting that p38 MAPK activation is an important initiating event in Nef-mediated PD-1 expression in HIV-1-infected cells. These data demonstrate an important signaling event of Nef in HIV-1 pathogenesis.

Schindler M, Schmökel J, Specht A, Li H, Münch J, Khalid M, Sodora DL, Hahn BH, Silvestri G, Kirchhoff F. · Institute of Virology, University of Ulm, Germany. · PLoS Pathog. · Pubmed #18636106 links to  free full text

Abstract: Recent data suggest that Nef-mediated downmodulation of TCR-CD3 may protect SIVsmm-infected sooty mangabeys (SMs) against the loss of CD4+ T cells. However, the mechanisms underlying this protective effect remain unclear. To further assess the role of Nef in nonpathogenic SIV infection, we cloned nef alleles from 11 SIVsmm-infected SMs with high (>500) and 15 animals with low (<500) CD4+ T-cells/microl in bulk into proviral HIV-1 IRES/eGFP constructs and analyzed their effects on the phenotype, activation, and apoptosis of primary T cells. We found that not only efficient Nef-mediated downmodulation of TCR-CD3 but also of MHC-I correlated with preserved CD4+ T cell counts, as well as with high numbers of Ki67+CD4+ and CD8+CD28+ T cells and reduced CD95 expression by CD4+ T cells. Moreover, effective MHC-I downregulation correlated with low proportions of effector and high percentages of naïve and memory CD8+ T cells. We found that T cells infected with viruses expressing Nef alleles from the CD4low SM group expressed significantly higher levels of the CD69, interleukin (IL)-2 and programmed death (PD)-1 receptors than those expressing Nefs from the CD4high group. SIVsmm Nef alleles that were less active in downmodulating TCR-CD3 were also less potent in suppressing the activation of virally infected T cells and subsequent cell death. However, only nef alleles from a single animal with very low CD4+ T cell counts rendered T cells hyper-responsive to activation, similar to those of HIV-1. Our data suggest that Nef may protect the natural hosts of SIV against the loss of CD4+ T cells by at least two mechanisms: (i) downmodulation of TCR-CD3 to prevent activation-induced cell death and to suppress the induction of PD-1 that may impair T cell function and survival, and (ii) downmodulation of MHC-I to reduce CTL lysis of virally infected CD4+ T cells and/or bystander CD8+ T cell activation.

Estes JD, Gordon SN, Zeng M, Chahroudi AM, Dunham RM, Staprans SI, Reilly CS, Silvestri G, Haase AT. · Department of Microbiology, Medical School, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA. · J Immunol. · Pubmed #18453600 links to  free full text

Abstract: Primate lentiviruses are typically apathogenic in their evolutionarily coadapted host species but can be lethal when transferred to new host species. Why such infections are pathogenic in humans and rhesus macaques (RMs) but not in sooty mangabeys (SMs), a natural host, remains unclear. Studies of chronically infected animals point to the importance of diminished immune activation in response to the infection in SMs. In this study, we sought the causes and timing of the differences in immune activation in a comparative study of acute SIV infection in RMs and SMs. Surprisingly, we show that in acute infection immune activation is comparable in SMs and RMs but thereafter, SMs quickly resolve immune activation, whereas RMs did not. Early resolution of immune activation in SMs correlated with increased expression of PD-1 and with preservation of CD4(+) T cell counts and lymphatic tissue architecture. These findings point to early control of immune activation by host immunoregulatory mechanisms as a major determinant of the different disease outcomes in SIV infection of natural vs non-natural hosts.

Kirchhoff F, Silvestri G. · Institute of Virology, University of Ulm, Ulm, Germany. · J Clin Invest. · Pubmed #18431512 links to  free full text

Abstract: HIV-associated hematological abnormalities involve all lineages of blood cells, thus implying that the virus impairs the function of early HSCs. However, the underlying mechanisms of this defect are unknown, particularly since HSCs are largely resistant to HIV-1 infection. In this issue of the JCI, Prost and colleagues show that the viral accessory protein Negative factor (Nef) plays a potentially critical role in the pathogenesis of HIV/SIV-associated hematopoietic dysfunction by affecting the clonogenic potential of HSCs (see the related article beginning on page 1765). Soluble Nef induces PPARgamma in uninfected HSCs, thereby suppressing the expression of STAT5A and STAT5B, two factors necessary for proper HSC function. The identification of this novel activity of extracellular Nef defines a new mechanism of HIV/SIV pathogenesis and suggests that approaches aimed at increasing STAT5A and STAT5B expression may be considered in HIV-infected individuals with prominent hematological abnormalities. The results also raise the question of whether dysregulation of hematopoiesis by extracellular Nef plays a role in the development of T cell immunodeficiency and the high levels of chronic immune activation associated with AIDS.

Dunham RM, Cervasi B, Brenchley JM, Albrecht H, Weintrob A, Sumpter B, Engram J, Gordon S, Klatt NR, Frank I, Sodora DL, Douek DC, Paiardini M, Silvestri G. · Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · J Immunol. · Pubmed #18390743 links to  free full text

Abstract: Decreased CD4(+) T cell counts are the best marker of disease progression during HIV infection. However, CD4(+) T cells are heterogeneous in phenotype and function, and it is unknown how preferential depletion of specific CD4(+) T cell subsets influences disease severity. CD4(+) T cells can be classified into three subsets by the expression of receptors for two T cell-tropic cytokines, IL-2 (CD25) and IL-7 (CD127). The CD127(+)CD25(low/-) subset includes IL-2-producing naive and central memory T cells; the CD127(-)CD25(-) subset includes mainly effector T cells expressing perforin and IFN-gamma; and the CD127(low)CD25(high) subset includes FoxP3-expressing regulatory T cells. Herein we investigated how the proportions of these T cell subsets are changed during HIV infection. When compared with healthy controls, HIV-infected patients show a relative increase in CD4(+)CD127(-)CD25(-) T cells that is related to an absolute decline of CD4(+)CD127(+)CD25(low/-) T cells. Interestingly, this expansion of CD4(+)CD127(-) T cells was not observed in naturally SIV-infected sooty mangabeys. The relative expansion of CD4(+)CD127(-)CD25(-) T cells correlated directly with the levels of total CD4(+) T cell depletion and immune activation. CD4(+)CD127(-)CD25(-) T cells were not selectively resistant to HIV infection as levels of cell-associated virus were similar in all non-naive CD4(+) T cell subsets. These data indicate that, during HIV infection, specific changes in the fraction of CD4(+) T cells expressing CD25 and/or CD127 are associated with disease progression. Further studies will determine whether monitoring the three subsets of CD4(+) T cells defined based on the expression of CD25 and CD127 should be used in the clinical management of HIV-infected individuals.

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.

Monceaux V, Viollet L, Petit F, Cumont MC, Kaufmann GR, Aubertin AM, Hurtrel B, Silvestri G, Estaquier J. · Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris cedex 15, France. · J Virol. · Pubmed #17898067 links to  free full text

Abstract: Simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) provides a reliable model to study the relationship between lentivirus replication, cellular immune responses, and CD4+ T-cell dynamics. Here we investigated, using SIVmac251-infected RMs of a Chinese genetic background (which experience a slower disease progression than Indian RMs), the dynamics of CD4+ CCR5+ T cells, as this subset of memory/activated CD4+ T cells is both a preferential target of virus replication and a marker of immune activation. As expected, we observed that the number of circulating CD4+ CCR5+ T cells decreases transiently at the time of peak viremia. However, at 60 days postinfection, i.e., when set-point viremia is established, the level of CD4+ CCR5+ T cells was increased compared to the baseline level. Interestingly, this increase correlated with faster disease progression, higher plasma viremia, and early loss of CD4+ T-cell function, as measured by CD4+ T-cell count, the fraction of memory CD4+ T cells, and the recall response to purified protein derivative. Taken together, these data show a key difference between the dynamics of the CD4+ CCR5+ T-cell pool (and its relationship with disease progression) in Chinese RMs and those described in previous reports for Indian SIVmac251-infected RMs. As the SIV-associated changes in the CD4+ CCR5+ T-cell pool reflect the opposing forces of SIV replication (which reduces this cellular pool) and immune activation (which increases it), our data suggest that in SIV-infected Chinese RMs the impact of immune activation is more prominent than that of virus replication in determining the size of the pool of CD4+ CCR5+ T cells in the periphery. As progression of HIV infection in humans also is associated with a relative expansion of the level of CD4+ CCR5+ T cells, we propose that SIV infection of Chinese RMs is a very valuable and important animal model for understanding the pathogenesis of human immunodeficiency virus infection.

Magnani M, Paiardini M, Cervasi B, Serafini S, Fraternale A, Silvestri G. · Institute of Biochemistry G. Fornini University of Urbino, Urbino (PU), Italy. · J Control Release. · Pubmed #17718963 No free full text.

This publication has no abstract.

Milush JM, Reeves JD, Gordon SN, Zhou D, Muthukumar A, Kosub DA, Chacko E, Giavedoni LD, Ibegbu CC, Cole KS, Miamidian JL, Paiardini M, Barry AP, Staprans SI, Silvestri G, Sodora DL. · University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. · J Immunol. · Pubmed #17709519 links to  free full text

Abstract: Peripheral blood CD4+ T cell counts are a key measure for assessing disease progression and need for antiretroviral therapy in HIV-infected patients. More recently, studies have demonstrated a dramatic depletion of mucosal CD4+ T cells during acute infection that is maintained during chronic pathogenic HIV as well as SIV infection. A different clinical disease course is observed during the infection of natural hosts of SIV infection, such as sooty mangabeys (Cercocebus atys), which typically do not progress to AIDS. Previous studies have determined that SIV+ mangabeys generally maintain healthy levels of CD4+ T cells despite having viral replication comparable to HIV-infected patients. In this study, we identify the emergence of a multitropic (R5/X4/R8-using) SIV infection after 43 or 71 wk postinfection in two mangabeys that is associated with an extreme, persistent (>5.5 years), and generalized loss of CD4+ T cells (5-80 cells/microl of blood) in the absence of clinical signs of AIDS. This study demonstrates that generalized CD4+ T cell depletion from the blood and mucosal tissues is not sufficient to induce AIDS in this natural host species. Rather, AIDS pathogenesis appears to be the cumulative result of multiple aberrant immunologic parameters that include CD4+ T cell depletion, generalized immune activation, and depletion/dysfunction of non-CD4+ T cells. Therefore, these data provide a rationale for investigating multifaceted therapeutic strategies to prevent progression to AIDS, even following dramatic CD4 depletion, such that HIV+ humans can survive normal life spans analogous to what occurs naturally in SIV+ mangabeys.