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HIV is a major driver of tuberculosis (TB) reactivation. Depletion of [CD4.sup.+] T cells is assumed to be the basis behind TB reactivation in individuals with latent tuberculosis infection (LTBI) coinfected with HIV. Nonhuman primates (NHPs) coinfected with a mutant simian immunodeficiency virus (SIV[DELTA]GY) that does not cause depletion of tissue [CD4.sup.+] T cells during infection failed to reactivate TB. To investigate the contribution of [CD4.sup.+] T cell depletion relative to other mechanisms of SIV-induced reactivation of LTBI, we used CD4R1 antibody to deplete [CD4.sup.+] T cells in animals with LTBI without lentiviral infection. The mere depletion of [CD4.sup.+] T cells during LTBI was insufficient in generating reactivation of LTBI. Instead, direct cytopathic effects of SIV resulting in chronic immune activation, along with the altered effector T cell phenotypes and dysregulated T cell homeostasis, were likely mediators of reactivation of LTBI. These results revealed important implications for TB control in HIV-coinfected individuals., Introduction Tuberculosis (TB) and HIV coinfection are a global syndemic (1). Approximately 90% of HIV-negative Mycobacterium tuberculosis-infected (Mtb-infected) individuals lack clinical signs of TB and are considered to have latent [...]

Apoptosis has been proposed as a key mechanism responsible for [CD4.sup.+] T cell depletion and immune dysfunction during HIV infection. We demonstrated that Q-VD-OPH, a caspase inhibitor, inhibits spontaneous and activation-induced death of T cells from SIV-infected rhesus macaques (RMs). When administered during the acute phase of infection, Q-VD-OPH was associated with (a) reduced levels of T cell death, (b) preservation of [CD4.sup.+]/[CD8.sup.+] T cell ratio in lymphoid organs and in the gut, (c) maintenance of memory [CD4.sup.+]T cells, and (d) increased specific [CD4.sup.+]T cell response associated with the expression of cytotoxic molecules. Although therapy was limited to the acute phase of infection, Q-VD-OPH-treated RMs showed lower levels of both viral load and cell-associated SIV DNA as compared with control SIV-infected RMs throughout the chronic phase of infection, and prevented the development of AIDS. Overall, our data demonstrate that Q-VD-OPH injection in SIV- infected RMs may represent an adjunctive therapeutic agent to control HIV infection and delaying disease progression to AIDS., Introduction Pathogenic HIV and SIV infections of humans and rhesus macaques (RMs), respectively, are associated with progressive [CD4.sup.+]T cell depletion and having a short half-life (1, 2). The regulation of [...]

A mutation in VRC01, a broadly neutralizing, HIV-1-specific antibody, confers enhanced binding to the neonatal Fc receptor, increasing the antibody half-life in the serum and localization in mucosal tissues, where it provides superior protection against rectal simian HIV-1 infection in macaques. Enhanced anti-HIV activity in mutant VRC01 antibody The recent discovery of broad and potent anti-HIV-1 antibodies has renewed interest in their use for passive protection against human immunodeficiency virus-1 in humans. This paper describes a mutation in the HIV-specific broadly neutralizing antibody VRC01 that confers enhanced binding to the neonatal Fc receptor and increases the antibody half-life in serum and mucosal tissues. It conferred superior protection in a rectal simian-HIV challenge model in macaques when compared to wild-type VRC01. 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 persistence of antibodies at these sites is influenced by the neonatal Fc receptor (FcRn).sup.1,2, whose role in protecting against infection in vivo has not been defined. Here, we show that a bnAb with enhanced FcRn binding has increased gut mucosal tissue localization, which improves protection against lentiviral infection in non-human primates. A bnAb directed to the CD4-binding site of the HIV-1 envelope (Env) protein (denoted VRC01).sup.3 was modified by site-directed mutagenesis to increase its binding affinity for FcRn. This enhanced FcRn-binding mutant bnAb, denoted VRC01-LS, displayed increased transcytosis across human FcRn-expressing cellular monolayers in vitro while retaining Fc[gamma]RIIIa binding and function, including antibody-dependent cell-mediated cytotoxicity (ADCC) activity, at levels similar to VRC01 (the wild type). VRC01-LS had a threefold longer serum half-life than VRC01 in non-human primates and persisted in the rectal mucosa even when it was no longer detectable in the serum. Notably, VRC01-LS mediated protection superior to that afforded by VRC01 against intrarectal infection with simian-human immunodeficiency virus (SHIV). These findings suggest that modification of FcRn binding provides a mechanism not only to increase serum half-life but also to enhance mucosal localization that confers immune protection. Mutations that enhance FcRn function could therefore increase the potency and durability of passive immunization strategies to prevent HIV-1 infection., Author(s): Sung-Youl Ko [sup.1] , Amarendra Pegu [sup.1] , Rebecca S. Rudicell [sup.1] [sup.6] , Zhi-yong Yang [sup.1] [sup.6] , M. Gordon Joyce [sup.1] , Xuejun Chen [sup.1] , Keyun [...]

Vaccines are largely evaluated for their ability to promote adaptive immunity, with little focus on the induction of negative immune regulators. Adjuvants facilitate and enhance vaccine-induced immune responses and have been explored for mediating protection against HIV. Using a regimen of peptide priming followed by a modified vaccinia Ankara (MVA) boost in a nonhuman primate model, we found that an SIV vaccine incorporating molecular adjuvants mediated partial protection against rectal SIVmac251 challenges. Animals treated with vaccine and multiple adjuvants exhibited a reduced viral load (VL) compared with those treated with vaccine only. Surprisingly, animals treated with adjuvant alone had reduced VLs that were comparable to or better than those of the vaccine-treated group. VL reduction was greatest in animals with the MHC class I allele Mamu-A*01 that were treated with adjuvant only and was largely dependent on [CD8.sup.+] T cells. Early VLs correlated with [Ki67.sup.+][CCR5.sup.+][CD4.sup.+] T cell frequency, while set-point VL was associated with expansion of a myeloid cell population that was phenotypically similar to myeloid-derived suppressor cells (MDSCs) and that suppressed T cell responses in vitro. MDSC expansion occurred in animals receiving vaccine and was not observed in the adjuvant-only group. Collectively, these results indicate that vaccine-induced MDSCs inhibit protective cellular immunity and suggest that preventing MDSC induction may be critical for effective AIDS vaccination., Introduction Recent studies showed that vaccine-induced T cell responses could control the replication of AIDS viruses and that the magnitude and function of virus-specific T cell responses correlated with protection [...]

CD[4.sup.+] T cells play a central role in the immunopathogenesis of HIV/AIDS, and their depletion during chronic HIV infection is a hallmark of disease progression. However, the relative contribution of [...]

Background: We developed a series of 30+ VSV-based constructs containing HIV-1 Env chimeras with or without SIV gag in absence of VSV-G and with or without the Ebola glycoprotein. After pre-clinical analyses of production/expression and small animal testing, a subset of 4 were used to immunize macaques that were later challenge with low dose SHIV. Methods: VSVdelG-based vectors were produced to express codon optimized HIV-1 ecto Env of NL4-3 or subtype A, strain 74 Env with N425K Env with different transmembrane and intracellular tails (TMIC) of the VSV G, Ebola GP, mutated HIV-1 and SIVmac239 Env. VSVdelG replication was driven either by the functional Env chimera or by cis addition of Ebola or Marburg GP. Expression and Env function for entry was tested and VSV vectors were produced for mouse immunizations to measure humoral (binding and neutralizing Abs) and CTL responses. The best candidates were then tested in rabbits and macaque challenge studies. Results: Details of the three year preclinical screening and subsequent correlates of protection for the best vaccine candidates will be provided in the presentation. The best candidate, VSVdelG_A74-gp140/SIV-TMIC_Ebola-GP was used as the prime followed by a boost with VSVdelG_SIV-Gag + A74-gp140/SIV-TMIC_Ebola-GP and then a boost with VSVdelG_A74-gp140/SIV-TMIC_Ebola_GP (Grp1). Eight of ten of the control macaques (Grp2) and 10 of 10 in an alternative vaccine regimen (Grp2) were infected with SHIV_SF162-p3 by the final low dose 7 challenges. Four of ten animals of the best performing vaccinated group were infected by challenge 7th. Conclusions: Building on the VSV-Ebola vaccine technology, we engineered/tested an improved VSV-based HIV vaccine and observed one of the best protections against low dose heterologous challenges in macaques to date. Findings also suggest that use of VSV-HIV_Env construct with Gag may be important for protection, especially in boosting CTL response, but its inclusion in the final boost (groups 2 and 4) may promote an activated CD4+ T cell population capable of increasing SHIV infection. These findings suggest an important balance of cell-based versus humoral immunity in prime/boost vaccine strategies for optimal protection. The current study is one of the first reports of meaningful cross-clade heterologous protection., OA12.04LB E. Arts (1); A. Berger (2); J. Pedersen (2); M.-A. Lafrance (2); J. Knapp (1); H. Azizi (2); Y. Li (1); F. Scholte (2); J. Mann (1); A. Kamen [...]

Natural nonhuman primate hosts of SIV do not succumb to AIDS despite significant viral replication, a phenomenon attributed to reduced levels of chronic and deleterious 'immune activation.' Two studies in this issue of the JCI, by Bosinger et al. and Jacquelin et al., now show that SIV induces vigorous immune activation and upregulation of IFN-stimulated genes in both natural and susceptible hosts, but strikingly, the responses resolve only in the former (see the related articles beginning on pages 3556 and 3544, respectively). Thus, natural hosts for SIV actively engage mechanisms to abort sustained immune activation and its associated harmful effects., Chronic, generalized immune activation is believed to advance the pathogenesis of progressive HIV and SIV infection (1), (2). The phenomenon, observed in humans and in susceptible strains of monkeys (e.g., [...]

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 [...]

The cell-mediated immune profile induced by a recombinant DNA vaccine was assessed in the simian/HIV (SHIV) and macaque model. The vaccine strategy included coimmunization of a DNA-based vaccine alone or in combination with an optimized plasmid encoding macaque IL-15 (pmacIL-15). We observed strong induction of vaccine-specific IFN-[gamma]-producing [CD8.sup.+] and [CD4.sup.+] effector T cells in the vaccination groups. Animals were subsequently challenged with 89.6p. The vaccine groups were protected from ongoing infection, and the IL-15 covaccinated group showed a more rapidly controlled infection than the group treated with DNA vaccine alone. Lymphocytes isolated from the group covaccinated with pmacIL-15 had higher cellular proliferative responses than lymphocytes isolated from the macaques that received SHIV DNA alone. Vaccine antigen activation of lymphocytes was also studied for a series of immunological molecules. Although mRNA for IFN-[gamma] was up-regulated after antigen stimulation, the inflammatory molecules IL-8 and MMP-9 were down-regulated. These observed immune profiles are potentially reflective of the ability of the different groups to control SHIV replication. This study demonstrates that an optimized IL-15 immune adjuvant delivered with a DNA vaccine can impact the cellular immune profile in nonhuman primates and lead to enhanced suppression of viral replication. HIV vaccine | immune response | cytokine adjuvant | T cell immunity

Research has been conducted on the use of simian immunodeficiency virus infection of rhesus macaques in investigating the role of selenium in AIDS. Results demonstrate that monkeys infected with simian immunodeficiency virus in vivo can be used for investigation of response mechanism of reduced selenium levels accompanying AIDS disease progression.

Young Rhesus monkeys infected with simian immunodeficiency virus (SIV) do not grow normally. In a group of young SIV-infected monkeys, viral load rather than CD4 T cell count seemed to be linked to failure to thrive. SIV is related to HIV, the virus that causes AIDS in humans.