Emergence of resistance mutations in simian immunodeficiency virus (SIV)-infected rhesus macaques receiving non-suppressive antiretroviral therapy (ART).
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ABSTRACT:
SUBMITTER: Policicchio BB
PROVIDER: S-EPMC5821307 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
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Project description:Antiretroviral therapy (ART) cannot eradicate human immunodeficiency virus (HIV) and a rapid rebound of virus replication follows analytical treatment interruption (ATI) in the vast majority of HIV-infected individuals. Sustained control of HIV replication without ART has been documented in a subset of individuals, defined as posttreatment controllers (PTCs). The key determinants of post-ART viral control remain largely unclear. Here, we identified 7 SIVmac239-infected rhesus macaques (RMs), defined as PTCs, who started ART 8 weeks postinfection, continued ART for >7?months, and controlled plasma viremia at <104 copies/ml for up to 8?months after ATI and <200 copies/ml at the latest time point. We characterized immunologic and virologic features associated with post-ART SIV control in blood, lymph node (LN), and colorectal (RB) biopsy samples compared to 15 noncontroller (NC) RMs. Before ART initiation, PTCs had higher CD4 T cell counts, lower plasma viremia, and SIV-DNA content in blood and LN compared to NCs, but had similar CD8 T cell function. While levels of intestinal CD4 T cells were similar, PTCs had higher frequencies of Th17 cells. On ART, PTCs had significantly lower levels of residual plasma viremia and SIV-DNA content in blood and tissues. After ATI, SIV-DNA content rapidly increased in NCs, while it remained stable or even decreased in PTCs. Finally, PTCs showed immunologic benefits of viral control after ATI, including higher CD4 T cell levels and reduced immune activation. Overall, lower plasma viremia, reduced cell-associated SIV-DNA, and preserved Th17 homeostasis, including at pre-ART, are the main features associated with sustained viral control after ATI in SIV-infected RMs.IMPORTANCE While effective, antiretroviral therapy is not a cure for HIV infection. Therefore, there is great interest in achieving viral remission in the absence of antiretroviral therapy. Posttreatment controllers represent a small subset of individuals who are able to control HIV after cessation of antiretroviral therapy, but characteristics associated with these individuals have been largely limited to peripheral blood analysis. Here, we identified 7 SIV-infected rhesus macaques that mirrored the human posttreatment controller phenotype and performed immunologic and virologic analysis of blood, lymph node, and colorectal biopsy samples to further understand the characteristics that distinguish them from noncontrollers. Lower viral burden and preservation of immune homeostasis, including intestinal Th17 cells, both before and after ART, were shown to be two major factors associated with the ability to achieve posttreatment control. Overall, these results move the field further toward understanding of important characteristics of viral control in the absence of antiretroviral therapy.
| S-EPMC7343203 | biostudies-literature
Project description:A retrospective neuropathologic review of 30 SIV-infected pigtailed macaques receiving combination antiretroviral therapy (cART) was conducted. Seventeen animals with lymphocyte-dominant inflammation in the brain and/or meninges that clearly was morphologically distinct from prototypic SIV encephalitis and human immunodeficiency virus encephalitis were identified. Central nervous system (CNS) infiltrates in cART-treated macaques primarily comprised CD20+ B cells and CD3+ T cells with fewer CD68+ macrophages. Inflammation was associated with low levels of SIV RNA in the brain as shown by in situ hybridization, and generally was observed in animals with episodes of cerebrospinal fluid (CSF) viral rebound or sustained plasma and CSF viremia during treatment. Although the lymphocytic CNS inflammation in these macaques shared morphologic characteristics with uncommon immune-mediated neurologic disorders reported in treated HIV patients, including CNS immune reconstitution inflammatory syndrome and neurosymptomatic CSF escape, the high prevalence of CNS lesions in macaques suggests that persistent adaptive immune responses in the CNS also may develop in neuroasymptomatic or mildly impaired HIV patients yet remain unrecognized given the lack of access to CNS tissue for histopathologic evaluation. Continued investigation into the mechanisms and outcomes of CNS inflammation in cART-treated, SIV-infected macaques will advance our understanding of the consequences of residual CNS HIV replication in patients on cART, including the possible contribution of adaptive immune responses to HIV-associated neurocognitive disorders.
| S-EPMC5745520 | biostudies-literature
Project description:Understanding HIV latent reservoirs in tissues is essential for the development of new strategies targeting these sites for eradication. Here, we assessed the size of latent reservoirs and the source of residual viruses in multiple lymphoid tissues of SIV-infected and fully suppressed rhesus macaques of Chinese-origin (cRMs). Eight cRMs were infected with SIVmac251 and treated with tenofovir and emtricitabine daily for 24 weeks initiated 4 weeks post-infection. Four of the eight animals reached sustained full viral suppression with undetectable viremia. The levels of cell-associated SIV DNA varied in peripheral blood mononuclear cells (PBMCs) and multiple lymphoid tissues, but with higher levels in the mesenteric lymph nodes (MesLNs). The levels of cell-associated SIV RNA also varied in different tissues. The higher frequency of viral RNA detection in the MesLNs was also observed by in situ hybridization. Consistently, the infection unit per million cells (IUPM) in the MesLNs was higher than in PBMCs and other tested lymphoid tissues by quantitative viral outgrowth assay (QVOA). Furthermore, env gp120 from tissue SIV RNA was amplified by single genome amplification. Phylogenetic analysis revealed diverse variants from tissues parallel to the viral inoculum in all viral suppressed animals. These results demonstrate that the latency and viral reservoirs in the lymphoid tissues still exist in aviremic macaques under full suppressive therapy. Moreover, the size of viral latent reservoirs differs in various lymphoid tissues with a relatively larger size in the MesLNs.
| S-EPMC6410399 | biostudies-literature
Project description:Herpes simplex virus 1 and 2 (HSV-1/2) similarly initiate infection in mucosal epithelia and establish lifelong neuronal latency. Anogenital HSV-2 infection augments the risk for sexual human immunodeficiency virus (HIV) transmission and is associated with higher HIV viral loads. However, whether oral HSV-1 infection contributes to oral HIV susceptibility, viremia, or oral complications of HIV infection is unknown. Appropriate non-human primate (NHP) models would facilitate this investigation, yet there are no published studies of HSV-1/SIV co-infection in NHPs. Thus, we performed a pilot study for an oral HSV-1 infection model in SIV-infected rhesus macaques to describe the feasibility of the modeling and resultant immunological changes. Three SIV-infected, clinically healthy macaques became HSV-1-infected by inoculation with 4 × 108 pfu HSV-1 McKrae on buccal, tongue, gingiva, and tonsils after gentle abrasion. HSV-1 DNA was shed in oral swabs for up to 21 days, and shedding recurred in association with intra-oral lesions after periods of no shedding during 56 days of follow up. HSV-1 DNA was detected in explant cultures of trigeminal ganglia collected at euthanasia on day 56. In the macaque with lowest baseline SIV viremia, SIV plasma RNA increased following HSV-1 infection. One macaque exhibited an acute pro-inflammatory response, and all three animals experienced T cell activation and mobilization in blood. However, T cell and antibody responses to HSV-1 were low and atypical. Through rigorous assessesments, this study finds that the virulent HSV-1 strain McKrae resulted in a low level HSV-1 infection that elicited modest immune responses and transiently modulated SIV infection.
| S-EPMC5723348 | biostudies-literature
Project description:Single-genome amplification (SGA) and sequencing of HIV-1 RNA in plasma of acutely infected humans allows the identification and enumeration of transmitted/founder viruses responsible for productive systemic infection. Use of this strategy as a means for identifying transmitted viruses suggested that intrarectal simian immunodeficiency virus (SIV) inoculation of macaques recapitulates key features of human rectal infection. However, no studies have used the SGA strategy to identify vaginally transmitted virus(es) in macaques or to determine how early SIV diversification in vaginally infected animals compares with HIV-1 in humans. We used SGA to amplify 227 partial env sequences from a SIVmac251 challenge stock and from seven rhesus macaques at the earliest plasma viral RNA-positive time point after low- and high-dose intravaginal inoculation. Sequences were analyzed phylogenetically to determine the relationship of transmitted/founder viruses within and between each animal and the challenge stock. In each animal, discrete low-diversity env sequence lineages were evident, and these coalesced phylogenetically to identical or near-identical env sequences in the challenge stock, thus confirming the validity of the SGA sequencing and modeling strategy for identifying vaginally transmitted SIV. Between 1 and 10 viruses were responsible for systemic infection, similar to humans infected by sexual contact, and the set of viruses transmitted to the seven animals studied represented the full genetic constellation of the challenge stock. These findings recapitulate many of the features of sexual HIV-1 transmission in women. Furthermore, the SIV rhesus macaque model can be used to understand the factors that influence the transmission of single versus multiple SIV variants.
| S-EPMC2898254 | biostudies-literature
Project description:Human cytomegalovirus (HCMV) possesses low pathogenic potential in an immunocompetent host. In the immunosuppressed host, however, a wide spectrum of infection outcomes, ranging from asymptomatic to life threatening, can follow either primary or nonprimary infection. The variability in the manifestations of HCMV infection in immunosuppressed individuals implies that there is a threshold of host antiviral immunity that can effectively limit disease potential. We used a nonhuman primate model of CMV infection to assess the relationship between CMV disease and the levels of developing anti-CMV immunity. Naive rhesus macaques were inoculated with rhesus cytomegalovirus (RhCMV) followed 2 or 11 weeks later by inoculation with pathogenic simian immunodeficiency virus SIVmac239. Two of four monkeys inoculated with SIV at 2 weeks after inoculation with RhCMV died within 11 weeks with simian AIDS (SAIDS), including activated RhCMV infection. Neither animal had detectable anti-SIV antibodies. The other two animals died 17 and 27 weeks after SIV inoculation with either SAIDS or early lymphoid depletion, although no histological evidence of activated RhCMV was observed. Both had weak anti-SIV antibody titers. RhCMV antibody responses for this group of monkeys were significantly below those of control animals inoculated with only RhCMV. In addition, all animals of this group had persistent RhCMV DNA in plasma and high copy numbers of RhCMV in tissues. In contrast, animals that were inoculated with SIV at 11 weeks after RhCMV infection rarely exhibited RhCMV DNA in plasma, had low copy numbers of RhCMV DNA in most tissues, and did not develop early onset of SAIDS or activated RhCMV. SIV antibody titers were mostly robust and sustained in these monkeys. SIV inoculation blunted further development of RhCMV humoral responses, unlike the normal pattern of development in control monkeys following RhCMV inoculation. Anti-RhCMV immunoglobulin G levels and avidity were slightly below control values, but levels maintained were higher than those observed following SIV infection at 2 weeks after RhCMV inoculation. These findings demonstrate that SIV produces long-lasting insults to the humoral immune system beginning very early after SIV infection. The results also indicate that anti-RhCMV immune development at 11 weeks after infection was sufficient to protect the host from acute RhCMV sequelae following SIV infection, in contrast to the lack of protection afforded by only 2 weeks of immune response to RhCMV. As previously observed, monkeys that were not able to mount a significant immune response to SIV were the most susceptible to SAIDS, including activated RhCMV infection. Rapid development of SAIDS in animals inoculated with SIV 2 weeks after RhCMV inoculation suggests that RhCMV can augment SIV pathogenesis, particularly during primary infection by both viruses.
| S-EPMC136401 | biostudies-literature
Project description:ObjectivesWe used simian immunodeficiency virus (SIV)-infected nonhuman primates to investigate longitudinal changes of brain volume caused by SIV and the effect of combined antiretroviral therapy (cART). In addition, the relation between viral load, immune status, and brain volume were explored.DesignA longitudinal study of two healthy controls, five SIVmac239-infected macaques received cART (SIV+cART+) at 40 days postinnoculation, and five SIVmac239-infected macaques received no therapy (SIV+cART-).MethodsStructural T1-weighted MRI, blood and cerebrospinal fluid testing were acquired at multiple time points for 48 weeks postinfection (wpi). Brain volume was estimated using region of interest (ROI)-based analysis. Volume differences were compared among three groups. Linear regression models tested the associations between brain volumes and biomarkers (viral load, CD4+ T-cell count, CD4+/CD8+ ratio).ResultsIn our model, brain volume alteration in SIV-infected macaques can be detected at 12 wpi in several brain regions. As the infection progresses, the SIV+cART- macaques displayed generalized gray matter atrophy at the endpoint. Though initiate cART right after acute infection, SIV+cART+ macaques still displayed brain atrophy but showed signs of reversibility. Plasma viral load is mainly associated with subcortical nucleus volume whereas CD4+ T-cell count and CD4+/CD8+ ratio in plasma were associated with widespread cortical volume.ConclusionThe SIVmac239-infected Chinese origin macaque is a valid model for neuroHIV. Brain atrophy caused by SIV infection can be relieved, even reversed, by cART. Our model also provides new insights into understanding the pathogenesis of brain injury in people with HIV (PWH).
| S-EPMC8631166 | biostudies-literature
Project description:To elucidate the mode of viral persistence in primate lentivirus-infected individuals during combination antiretroviral therapy (cART), four simian immunodeficiency virus 239-infected monkeys were treated with cART for 1 year. The viral env genes prepared from total RNA extracted from the mesenteric lymph nodes collected at the completion of therapy were assessed by single genome amplification. Analyses of nucleotide substitutions and phylogeny revealed no viral evolution during cART.
| S-EPMC3624378 | biostudies-literature
Project description:BackgroundAn effective AIDS vaccine remains one of the highest priorities in HIV-research. Our recent study showed that vaccination of rhesus macaques with recombinant simian varicella virus (rSVV) vector - simian immunodeficiency virus (SIV) envelope and gag genes, induced neutralizing antibodies and cellular immune responses to SIV and also significantly reduced plasma viral loads following intravenous pathogenic challenge with SIVMAC251/CX1.FindingsThe purpose of this study was to define cellular immunological correlates of protection in rSVV-SIV vaccinated and SIV challenged animals. Immunofluorescent staining and multifunctional assessment of SIV-specific T-cell responses were evaluated in both Experimental and Control vaccinated animal groups. Significant increases in the proliferating CD4+ T-cell population and polyfunctional T-cell responses were observed in all Experimental-vaccinated animals compared with the Control-vaccinated animals.ConclusionsIncreased CD4+ T-cell proliferation was significantly and inversely correlated with plasma viral load. Increased SIV-specific polyfunctional cytokine responses and increased proliferation of CD4+ T-cell may be crucial to control plasma viral loads in vaccinated and SIVMAC251/CX1 challenged macaques.
| S-EPMC3485174 | biostudies-literature
Project description:Lentiviral replication in its target cells affects a delicate balance between cellular cofactors required for virus propagation and immunoregulation for host defense. To better elucidate cellular proteins linked to viral infection, we tested plasma from rhesus macaques infected with the simian immunodeficiency viral strain SIVsmm9, prior to, 10 days (acute), and 49 weeks (chronic) after viral infection. Changes in plasma protein content were measured by quantitative mass spectrometry by isobaric tags for absolute and relative quantitation (iTRAQ) methods. An 81 and 232% increase in SERPINA1 was seen during acute and chronic infection, respectively. Interestingly, gelsolin, vitamin D binding protein and histidine rich glycoprotein were decreased by 45% in acute conditions but returned to baseline during chronic infection. When compared to uninfected controls, a 48-103% increase in leucine rich alpha 2-glycoprotein, vitronectin, and ceruloplasmin was observed during chronic viral infection. Observed changes in plasma proteins expression likely represent a compensatory host response to persistent viral infection.
| S-EPMC3285256 | biostudies-literature