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Intestinal microbial dysbiosis has been described in individuals with an HIV-1 infection and may underlie persistent inflammation in chronic infection, thereby contributing to disease progression. Herein, we induced an HIV-1-like intestinal dysbiosis in rhesus macaques (Macaca mulatta) with vancomycin treatment and assessed the contribution of dysbiosis to SIV disease progression. Dysbiotic and control animals had similar disease progression, indicating that intestinal microbial dysbiosis similar to that observed in individuals with HIV is not sufficient to accelerate untreated lentiviral disease progression. Antibiotic treatment of SIV-infected nonhuman primates shows that inducing bacterial dysbiosis in the gut--similar to that seen in HIV infection--does not promote disease progression, questioning its potential role in progression to HIV/AIDS., Author(s): Alexandra M. Ortiz [sup.1] , Jacob K. Flynn [sup.1] , Sarah R. DiNapoli [sup.1] , Ivan Vujkovic-Cvijin [sup.2] , Carly E. Starke [sup.1] , Stephen H. Lai [sup.1] , [...]

LN follicles constitute major reservoir sites for HIV/SIV persistence. Cure strategies could benefit from the characterization of [CD8.sup.+] T cells able to access and eliminate HIV-infected cells from these areas. In this study, we provide a comprehensive analysis of the phenotype, frequency, localization, and functionality of follicular [CD8.sup.+] T cells (f[CD8.sup.+]) in SIV-infected nonhuman primates. Although disorganization of follicles was a major factor, significant accumulation of f[CD8.sup.+] cells during chronic SIV infection was also observed in intact follicles, but only in pathogenic SIV infection. In line with this, tissue inflammatory mediators were strongly associated with the accumulation of f[CD8.sup.+] cells, pointing to tissue inflammation as a major factor in this process. These f[CD8.sup.+] cells have cytolytic potential and can be redirected to target and kill HIV-infected cells using bispecific antibodies. Altogether, our data support the use of SIV infection to better understand the dynamics of f[CD8.sup.+] cells and to develop bispecific antibodies as a strategy for virus eradication., Introduction The ability of [CD8.sup.+] T cells to clear virus-infected, including HIV-infected, cells depends on the ability of [CD8.sup.+] T cells to migrate to sites of active virus replication (1-3). [...]

Natural killer (NK) cells play an essential role in antiviral immunity, but knowledge of their function in secondary lymphoid organs is incomplete. Lymph node follicles constitute a major viral reservoir during infections with HIV-1 and simian immunodeficiency virus of macaques (SIVmac). In contrast, during nonpathogenic infection with SIV from African green monkeys (SIVagm), follicles remain generally virus free. We show that NK cells in secondary lymphoid organs from chronically SIVagm-infected African green monkeys (AGMs) were frequently CXCR5[sup.+] and entered and persisted in lymph node follicles throughout the follow-up (240 d post-infection). These follicles were strongly positive for IL-15, which was primarily presented in its membrane-bound form by follicular dendritic cells. NK cell depletion through treatment with anti-IL-15 monoclonal antibody during chronic SIVagm infection resulted in high viral replication rates in follicles and the T cell zone and increased viral DNA in lymph nodes. Our data suggest that, in nonpathogenic SIV infection, NK cells migrate into follicles and play a major role in viral reservoir control in lymph nodes., Author(s): Nicolas Huot [1, 2]; Beatrice Jacquelin [1]; Thalia Garcia-Tellez [1]; Philippe Rascle [1, 2, 3]; Mickaël J Ploquin [1]; Yoann Madec [4]; R Keith Reeves [5]; Nathalie Derreudre-Bosquet [6]; [...]

YTE YTE 0.95 4.61 4.82, To protect against human immunodeficiency virus (HIV-1) infection, broadly neutralizing antibodies (bnAbs) must be active at the portals of viral entry in the gastrointestinal or cervicovaginal tracts. The localization and [...]

Background: It has been reported that positron emission tomography (PET) with anti-ENV monoclonal antibodies (mAbs) can be used to non-invasively image SIV in tissues of chronically infected as well as [...]

Hyperimmune activation is a strong predictor of disease progression during pathogenic immunodeficiency virus infections and is mediated in part by sustained type I IFN signaling in response to adventitious microbial infection. The immune inhibitory receptor programmed death-1 (PD-1) regulates functional exhaustion of virus-specific [CD8.sup.+] T cells during chronic infections, and in vivo PD-1 blockade has been shown to improve viral control of SIV. Here, we show that PD-1 blockade during chronic SIV infection markedly reduced the expression of transcripts associated with type I IFN signaling in the blood and colorectal tissue of rhesus macaques (RMs). The effect of PD-1 blockade on type I IFN signaling was durable and persisted even under conditions of high viremia. Reduced type I IFN signaling was associated with enhanced expression of some of the junction-associated genes in colorectal tissue and with a profound decrease in plasma LPS levels, suggesting a possible repair of gut-associated junctions and decreased microbial translocation into the blood. PD-1 blockade enhanced immunity to gut-resident pathogenic bacteria, control of gut-associated opportunistic infections, and survival of SIV-infected RMs. Our results suggest PD-1 blockade as a potential novel therapeutic approach to enhance combination antiretroviral therapy by suppressing hyperimmune activation in HIV-infected individuals., Introduction The immune inhibitory receptor programmed death-1 (PD-1) plays an important role in regulating functional exhaustion of virus-specific CD8+ T cells during chronic infections (1). Studies in mice demonstrated that [...]

Golgi dysfunction has been previously investigated as a mechanism involved in monocrotaline-induced pulmonary hypertension (PAH). In the present study, we addressed whether Golgi dysfunction might occur in pulmonary vascular cells in idiopathic PAH (IPAH) and whether there might be a causal relationship between trafficking dysfunction and vasculopathies of PAH. Quantitative immunostaining for the Golgi tethers giantin and p115 on human lung tissue from patients with IPAH (n = 6) compared with controls demonstrated a marked cytoplasmic dispersal of giantin- and p115-bearing vesicular elements in vascular cells in the proliferative, obliterative, and plexiform lesions in IPAH and an increase in the amounts of these Golgi tethers/matrix proteins per cell. The causality question was approached by genetic means using human immunodeficiency virus (HIV)-Nef, a protein that disrupts endocytic and trans-Golgi trafficking. Macaques infected with a chimeric simian immunodeficiency virus (SIV) containing the HIV-nefgene (SHIV-nef, but not the nonchimeric SIV virus containing the endogenous SIV-nef gene, displayed pulmonary arterial vasculopathies similar to those in human IPAH. Giantin and p115 levels and their subcellular distribution in pulmonary vascular cells in lungs of SHIV-nef infected macaques (n = 4) were compared with SIV-infected (n = 3) and an uninfected macaque control. Only macaques infected with chimeric SHIV-nef showed pulmonary vascular lesions containing cells with dramatic cytoplasmic dispersal and an increase in giantin and p115. Specifically, the HIV-Nef-positive cells showed increased giantin, p115, and the activated transcription factor PY-STAT3. These data represent the first test of the Golgi dysfunction hypothesis in IPAH and place trafficking and Golgi disruption in the chain of causality of pulmonary vasculopathies in the macaque model. pulmonary arterial hypertension; endothelial cells; smooth muscle cells; intra-Golgi tethers; human immuodeficiency virus; giantin; p115; signal transducer and activator of transcription 3 doi: 10.1152/ajplung.00087.2009

The precise immunological role played by [CD4.sup.+] T cells in retroviral infections is poorly defined. Here, we describe a new function of these cells, the elimination of retrovirus-infected macrophages. After experimental [CD8.sup.+] cell depletion, elite controlling macaques with set-point viral loads [less than or equal to] 500 viral RNA copies/mL mounted robust Gag-and Nef-specific [CD4.sup.+] T cell responses during reestablishment of control with [greater than or equal to] 54% of all virus-specific [CD4.sup.+] T cells targeting these 2 proteins. Ex vivo, these simian immunodeficiency virus (SIV)-specific [CD4.sup.+] T cells neither recognized nor suppressed viral replication in SIV-infected [CD4.sup.+] T cells. In contrast, they recognized SIV-infected macrophages as early as 2 h postinfection because of presentation of epitopes derived from virion-associated Gag and Nef proteins. Furthermore, virus-specific [CD4.sup.+] T cells displayed direct effector function and eliminated SIV-infected macrophages. These results suggest that retrovirus-specific [CD4.sup.+] T cells may contribute directly to elite control by inhibiting viral replication in macrophages. antigen processing and presentation | HIV

Chronic immunodeficiency virus infections are characterized by dysfunctional cellular and humoral antiviral immune responses (1-3). 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) (4,5) 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 (~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., Virus-specific T cells show varying degrees of functional impairment during chronic infections (6,7). Although these T cells retain some antiviral functions, they are less polyfunctional compared with antiviral T cells [...]

Cross-species transmission of retroviruses is common in Cameroon. To determine risk for simian T-cell lymphotropic virus (STLV) transmission from nonhuman primates to hunters, we examined 170 hunter-collected dried blood spots [...]

Naturally SIV-infected sooty mangabeys (SMs) remain asymptomatic despite high virus replication. Elucidating the mechanisms underlying AIDS resistance of SIV-infected SMs may provide crucial information to better understand AIDS pathogenesis. In this study, we assessed the determinants of set-point viremia in naturally SIV-infected SMs, i.e., immune control of SIV replication versus target cell limitation. We depleted [CD4.sup.+] T cells in 6 naturally SIV-infected SMs by treating with humanized anti-CD4 mAb (Cdr-OKT4A-huIgG1). [CD4.sup.+] T cells were depleted almost completely in blood and BM and at variable levels in mucosal tissues and LNs. No marked depletion of [CD14.sup.+] monocytes was observed. Importantly, [CD4.sup.+] T cell depletion was associated with a rapid, significant decline in viral load, which returned to baseline level at day 30-45, coincident with an increased fraction of proliferating and activated [CD4.sup.+] T cells. Throughout the study, virus replication correlated with the level of proliferating [CD4.sup.+] T cells. [CD4.sup.+] T cell depletion did not induce any changes in the fraction of Tregs or the level of SIV-specific [CD8.sup.+] T cells. Our results suggest that the availability of activated [CD4.sup.+] T cells, rather than immune control of SIV replication, is the main determinant of set-point viral load during natural SIV infection of SMs., Introduction The HIV epidemic in humans arose after zoonotic transmission of simian [CD4.sup.+] T cell tropic lentiviruses, which naturally infect a range of African monkey host species and are now [...]

Although HIV is the necessary and sufficient causative agent of AIDS, genetic and environmental factors markedly influence the pace of disease progression. Clinical and experimental evidence suggests that human herpesvirus 6A (HHV-6A), a cytopathic T-lymphotropic DNA virus, fosters the progression to AIDS in synergy with HIV-1. In this study, we investigated the effect of coinfection with HHV-6A on the rogression of simian immunodeficiency virus (SIV) disease in pig-tailed macaques (Macaca nemestrina). Inoculation of HHV-6A resulted in a rapid appearance of plasma viremia associated with transient clinical manifestations and followed by antibody seroconversion, indicating that this primate species is susceptible to HHV-6A infection. Whereas animals infected with HHV-6A alone did not show any long-term clinical and immunological sequelae, a progressive loss of CD[4.sup.+] T cells was observed in all of the macaques inoculated with SIV. However, progression to full-blown AIDS was dramatically accelerated by coinfection with HHV-6A. Rapid disease development indually infected animals was heralded by an early depletion of both CD[4.sup.+] and CD[8.sup.+] T cells. These results provide in vivo evidence that HHV-6A may act as a promoting factor in AIDS progression. simian immunodeficiency virus | animal models | herpesviruses

The narrow host range of human immunodeficiency virus type 1 (HIV-1) is caused in part by innate cellular factors such as apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) and TRIM5[alpha], which restrict virus replication in monkey cells. Variant HIV-1 molecular clones containing both a 21-nucleotide simian immunodeficiency virus (SIV) Gag CA element, corresponding to the HIV-1 cyclophilin A-binding site, and the entire SIV vif gene were constructed. Long-term passage in a cynomolgus monkey lymphoid cell line resulted in the acquisition of two nonsynonymous changes in env, which conferred improved replication properties. A proviral molecular clone, derived from infected cells and designated NL-DT5R, was used to generate virus stocks capable of establishing spreading infections in the cynomolgus monkey T cell line and CD8-depleted peripheral blood mononuclear cells from five of five pig-tailed macaques and one of three rhesus monkeys. NL-DT5R, which genetically is >93% HIV-1, provides the opportunity, not possible with currently available SIV/HIV chimeric viruses, to analyze the function of multiple HIV-1 genes in a broad range of nonhuman primate species. APOBEC3 | host range | monkey model | TRIM5[alpha] cyclophilin A

Simian HIV infection of macaques with CXCR4 tropic viruses results in early and profound CD4(super +) T-cell depletion in the first few weeks of infection. The dynamics of the interaction of virus and CD4(super +) cells are modeled over time to investigate the rate of CD4(super -) T-cell infection and death and it is indicated that the proportion of CD4(super -) cells destroyed is correlated with the peak viral load.

A study on the precise effect of alcohol addiction on HIV pathogenesis is designed to determine the effect of alcohol dependence on virus replication and CD4 profiles in simian immunodeficiency virus/simian-HIV-infected rhesus macaques. The extent of CD4 cell loss in the alcohol group is significantly higher than in the control animals at week 1 after infection.

The nef gene of human and simian immunodeficiency viruses (HIV and SIV) is important for pathogenicity and maintenance of high virus loads. We previously reported that recombinant vaccinia viruses (rVVs) expressing nef from attenuated SIVmac1A11 (vNef1A11) produced typical plaques on thymidine kinase-deficient 143B cells, whereas rVVs expressing nef derived from the pathogenic SIVmac239 (vNef157) formed plaques with altered morphology. Here, we show that vNef157 is attenuated in normal and nude mice, whereas the pathogenicity of vNeflA11 is similar to that of a control virus. Thus, Nef157 is an attenuating factor in the vaccinia virus (VV) system, contrasting sharply with its function in lentiviruses. We also show that Nef157 inhibits VV cell-to-cell spread, causing formation of atypical plaques regardless of thymidine kinase deficiency, neoplasticity, and species of the infected cell line. We hypothesized that Nef157 interferes with VV spread by association with actin, but no direct colocalization of Nef and the cytoskeletal actin network was detected. Instead, higher levels of Nef157 protein were observed, although mRNAs for both nef genes were produced at comparable levels. Thus, the mechanism behind such Nef157 protein accumulation and Nef157-mediated VV attenuation could be related to the process that causes an opposite effect in its native SIV system, making SIVmac239 more pathogenic than SIVmac1A11. attenuation | atypical plaque formation | lentiviruses | poxviruses | virulence

Unlike HIV-1 and simian immunodeficiency virus (SIV), which induce a slow, unrelenting loss of immune function spanning several years, highly pathogenic simian-human immunodeficiency viruses (SHIVs) induce a rapid, complete, and irreversible depletion of CD[4.sup.+] T lymphocytes in rhesus monkeys within weeks of infection, leading to death from immunodeficiency. We recently reported that, because these SHIVs exclusively use the CXCR4 coreceptor for cell entry, they target naive CD[4.sup.+] T cells for depletion in infected monkeys, whereas SIVs, which use CCR5, not CXCR4, cause the selective loss of memory C[D.sup.4+] T lymphocytes in vivo. Here we show both by DNA PCR analyses and infectivity assays, using live sorted CD[4.sup.+] T lymphocyte subsets, that 30-90% of circulating naive cells were productively infected by day 10 after inoculation. This result implies that direct cell killing, not bystander apoptosis, is responsible for the massive loss of CD[4.sup.+] T cells in the X4-tropic SHIV model. Furthermore, we directly demonstrate that >96% of virus producing cells did not express the Ki-67 proliferation marker on day 10 after inoculation using confocal microscopic analysis of lymph nodes samples. This finding is consistent with the prodigious levels of plasma viremia measured during acute X4-tropic SHIV infections of macaques being generated almost entirely by resting naive CD[4.sup.+] T cells. acute infection | animal model | CXCR4-tropic SHIV | HIV pathogenesis

Humoral immune response in the milk and plasma of 14 female rhesus macaques with suckling infants was characterized as a model of breast milk transmission of HIV. The observations indicate that the SIV-macaque model provides a unique resource for deciphering the functional role of antibodies in breast milk transmission of HIV and the observations are comparable with those for HIV-infected women.

In order to test pediatric vaccine candidates aimed at reducing HIV transmission through breast-feeding, an infant macaque model was developed. The results suggest that immunization of human infants with poxvirus-based HIV vaccine candidates may offer protection against early and late HIV infection through breastfeeding.

Given the dual role of CD4 T cells as both immune effectors and targets for HIV infection, the balance of CD4 versus CD8 T cell-mediated responses induced by candidate AIDS vaccines may be critical in determining postvaccination infection outcomes. An attenuated recombinant varicella-zoster virus vaccine expressing the simian immunodeficiency virus (SIV) envelope (Env) elicited nonneutralizing Env-binding antibodies and little if any cytotoxic T lymphocyte responses in rhesus macaques (Macaca mulatta). After challenge with SIV, Env vaccinees manifested increased levels of SIV replication, more rapid CD4 depletion, and accelerated progression to AIDS compared with controls. Enhanced SIV replication correlated with increased CD4 T cell proliferation soon after SIV challenge, apparently the result of an anamnestic response to SIV antigens. Thus activation of virus-specific CD4 T cells at the time of exposure to a CD4 T cell-tropic lentivirus, in the absence of an effective CD8 response, may enhance virus replication and disease. These data suggest suggest that candidate AIDS vaccines may not simply be either efficacious or neutral; they may also have the potential to be harmful.