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(A) CTL activity of a T1/T2
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Identification of the components of protective immunity are crucial for the development of effective prophylactic and therapeutic vaccine strategies. Analysis of HIV-specific responses in exposed but uninfected individuals might thus provide a unique resource to elucidate the components and correlates of protective immunity to HIV. In the present s...
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Context 1
... A representative negative CTL assay on env-stimulated cultures of an individual exposed to an HIV uninfected sample is shown in Fig. 1 H. To investigate the HLA restriction of these responses, CTL activity of stimulated cultures were assayed against peptide- pulsed HLA class I-mismatched targets in some individual cases (for example, donor 2) (Fig. 2 A.) No HIV-specific cytolytic activity of env-stimulated cultures was observed against heterol- ogous EBV-transformed mismatched targets pulsed with the stimulatory peptide. In addition, there was complete inhibition of env-specific lysis of autologous peptide-pulsed targets in the presence of the anti-class I monoclonal antibody (W6/32) ...
Context 2
... No HIV-specific cytolytic activity of env-stimulated cultures was observed against heterol- ogous EBV-transformed mismatched targets pulsed with the stimulatory peptide. In addition, there was complete inhibition of env-specific lysis of autologous peptide-pulsed targets in the presence of the anti-class I monoclonal antibody (W6/32) (do- nor 4) (Fig. 2 B) E:T responders shared HLA-A2 and all three recognized the TI /T2 pool of peptides. The lack of cytolytic activity of peptide-stimulated cultures on RPMI-pulsed targets, in addition to the fact that CTL re- sponses to env peptides were observed upon stimulation with only certain peptides and not others, suggest that these responses are ...
Citations
... Several groups have screened HESNs for the presence of adaptive HIV-specific T cells and antibody responses. Such responses have been found in many but not all cohorts of HESN subjects [2][3][4][5][6][7]. HIV-specific T cell responses in HESN were often of a low breadth and magnitude, and their presence did not always predict maintenance of seronegative status [8][9][10][11][12]. ...
Some people, known as HIV-exposed seronegative (HESN) individuals, remain uninfected despite high levels of exposure to HIV. Understanding the mechanisms underlying their apparent resistance to HIV infection may inform strategies designed to protect against HIV infection. Natural Killer (NK) cells are innate immune cells whose activation state depends on the integration of activating and inhibitory signals arising from cell surface receptors interacting with their ligands on neighboring cells. Inhibitory NK cell receptors use a subset of major histocompatibility (MHC) class I antigens as ligands. This interaction educates NK cells, priming them to respond to cells with reduced MHC class I antigen expression levels as occurs on HIV-infected cells. NK cells can interact with both autologous HIV-infected cells and allogeneic cells bearing MHC antigens seen as non self by educated NK cells. NK cells are rapidly activated upon interacting with HIV-infected or allogenic cells to elicit anti-viral activity that blocks HIV spread to new target cells, suppresses HIV replication, and kills HIV-infected cells before HIV reservoirs can be seeded and infection can be established. In this manuscript, we will review the epidemiological and functional evidence for a role for NK cells in protection from HIV infection.
... Although current cART is very effective in targeting HIV pathogenesis, the pervasive nature of this disease requires the continued development of new ways to target viral replication and improve immune function. A focus on understanding the mechanisms of HIV-1 suppression by those with the innate ability to control the virus (Clerici et al., 1992;Kelker et al., 1992;Cao et al., 1995;Huang et al., 1995;Pinto et al., 1995;Rowland-Jones et al., 1995;Fowke et al., 1996;Lefrère et al., 1999;Shacklett, 2006;Dyer et al., 2008;Pereyra et al., 2008;Gonzalo-Gil et al., 2017;Pernas et al., 2018;Lopez-Galindez et al., 2019;Nguyen et al., 2019;Macatangay et al., 2020) has the potential to identify novel ways to improve host immune function, give insight into immune mechanisms that are common to both chronic infection and cancer, and rapidly treat PLWH with FDA approved therapies. As cells harboring reactivated proviruses by LRAs would then be required to be eliminated by CTL, the combination therapy with LRAs and ICBs/CAR-T could achieve a functional HIV-1 cure for chronic HIV infection (Figure 5). ...
Although HIV-1 replication can be efficiently suppressed to undetectable levels in peripheral blood by combination antiretroviral therapy (cART), lifelong medication is still required in people living with HIV (PLWH). Life expectancies have been extended by cART, but age-related comorbidities have increased which are associated with heavy physiological and economic burdens on PLWH. The obstacle to a functional HIV cure can be ascribed to the formation of latent reservoir establishment at the time of acute infection that persists during cART. Recent studies suggest that some HIV reservoirs are established in the early acute stages of HIV infection within multiple immune cells that are gradually shaped by various host and viral mechanisms and may undergo clonal expansion. Early cART initiation has been shown to reduce the reservoir size in HIV-infected individuals. Memory CD4+ T cell subsets are regarded as the predominant cellular compartment of the HIV reservoir, but monocytes and derivative macrophages or dendritic cells also play a role in the persistent virus infection. HIV latency is regulated at multiple molecular levels in transcriptional and post-transcriptional processes. Epigenetic regulation of the proviral promoter can profoundly regulate the viral transcription. In addition, transcriptional elongation, RNA splicing, and nuclear export pathways are also involved in maintaining HIV latency. Although most proviruses contain large internal deletions, some defective proviruses may induce immune activation by expressing viral proteins or producing replication-defective viral-like particles. In this review article, we discuss the state of the art on mechanisms of virus persistence in the periphery and tissue and summarize interdisciplinary approaches toward a functional HIV cure, including novel capabilities and strategies to measure and eliminate the infected reservoirs and induce immune control.
... Effective HIV-1 therapy confirmed that control of viremia prevented CD4 + T-cell loss and even allowed some CD4 + T-cell recovery in most cases. In support of this, it was found that the viral loads in LTNP cohorts varied from below average to undetectable (Pinto et al., 1995;García et al., 1997). ...
... Subjects who maintained low, but still detectable viral load remained LTNPs. Infected individuals with undetectable viral loads (<50 RNA copies/ml) began to be appreciated as a separate group (Clerici et al., 1992;Kelker et al., 1992;Cao et al., 1995;Pinto et al., 1995;Rowland-Jones et al., 1995;Fowke et al., 1996;Rowland-Jones et al., 1998;Lefrère et al., 1999;Pereyra et al., 2008). In the 2000's, researchers began focusing on these subjects. ...
A unique population of HIV-1 infected individuals can control infection without antiretroviral therapy. These individuals fall into a myriad of categories based on the degree of control (low or undetectable viral load), the durability of control over time and the underlying mechanism (i.e., possession of protective HLA alleles or the absence of critical cell surface receptors). In this study, we examine a cohort of HIV-1 infected individuals with a documented history of sustained low viral loads in the absence of therapy. Through in vitro analyses of cells from these individuals, we have determined that infected individuals with naturally low viral loads are capable of controlling spreading infection in vitro in a CD8 ⁺ T-cell dependent manner. This control is lost when viral load is suppressed by antiretroviral therapy and correlates with a clinical CD4:CD8 ratio of <1. Our results support the conclusion that HIV-1 controllers with low, but detectable viral loads may be controlling the virus due to an effective CD8 ⁺ T-cell response. Understanding the mechanisms of control in these subjects may provide valuable understanding that could be applied to induce a functional cure in standard progressors.
... Thus, an alternative strategy to increase the potency with which Abs may destroy infected cells focuses upon addressing the limitations of T-cell-mediated responses. Effective cytotoxic T-cell responses have been associated with viral control in studies of relatively rare long-term non-progressors (198,199) and HIVexposed seronegative individuals (200). Similarly, persistent viral suppression after Ab therapy in a subset of SHIV-infected macaques (3 out of 18) was associated with improved host virusspecific cytotoxic T-lymphocyte (CTL) responses (13). ...
Preclinical and early human clinical studies of broadly neutralizing antibodies (bNAbs) to prevent and treat HIV infection support the clinical utility and potential of bNAbs for prevention, postexposure prophylaxis, and treatment of acute and chronic infection. Observed and potential limitations of bNAbs from these recent studies include the selection of resistant viral populations, immunogenicity resulting in the development of antidrug (Ab) responses, and the potentially toxic elimination of reservoir cells in regeneration-limited tissues. Here, we review opportunities to improve the clinical utility of HIV Abs to address these challenges and further accomplish functional targets for anti-HIV Ab therapy at various stages of exposure/infection. Before exposure, bNAbs’ ability to serve as prophylaxis by neutralization may be improved by increasing serum half-life to necessitate less frequent administration, delivering genes for durable in vivo expression, and targeting bNAbs to sites of exposure. After exposure and/or in the setting of acute infection, bNAb use to prevent/reduce viral reservoir establishment and spread may be enhanced by increasing the potency with which autologous adaptive immune responses are stimulated, clearing acutely infected cells, and preventing cell–cell transmission of virus. In the setting of chronic infection, bNAbs may better mediate viral remission or “cure” in combination with antiretroviral therapy and/or latency reversing agents, by targeting additional markers of tissue reservoirs or infected cell types, or by serving as targeting moieties in engineered cell therapy. While the clinical use of HIV Abs has never been closer, remaining studies to precisely define, model, and understand the complex roles and dynamics of HIV Abs and viral evolution in the context of the human immune system and anatomical compartmentalization will be critical to both optimize their clinical use in combination with existing agents and define further strategies with which to enhance their clinical safety and efficacy.
... In the same line, there are other individuals that, despite having being exposed to the virus for long periods of time, are resistant to HIV infection (Rowland-Jones and McMichael, 1995). This phenomenon was observed among (i) heterosexual partners of HIV infected people (Ranki et al., 1989;Langlade-Demoyen et al., 1994), (ii) sex workers Fowke et al., 1996), (iii) men who have sex with men, (iv) intravenous drug users, (v) exposed uninfected infants (Rowland-Jones et al., 1993;Cheynier et al., 1992) and, (vi) health-care workers (Clerici et al., 1994;Pinto et al., 1995). The mechanisms that allow these individuals to be "protected" from the virus are still unknown, although several hypotheses have been proposed. ...
As the HIV/AIDS pandemic still progresses, understanding the mechanisms governing viral transmission as well as protection from HIV acquisition is fundamental. In this context, cohorts of HIV serodiscordant heterosexual couples (SDC) represent a unique tool. The present study was aimed to evaluate specific parameters of innate, cellular and humoral immune responses in SDC. Specifically, plasma levels of cytokines and chemokines, HIV-specific T-cell responses, gp120-specific IgG and IgA antibodies, and HIV-specific antibody-dependent cellular cytotoxicity (ADCC) activity were assessed in nine HIV-exposed seronegative individuals (ESN) and their corresponding HIV seropositive partners (HIV(+)-P), in eighteen chronically infected HIV subjects (C), nine chronically infected subjects known to be HIV transmitters (CT) and ten healthy HIV(-) donors (HD). Very low magnitude HIV-specific cellular responses were found in two out of six ESN. Interestingly, HIV(+)-P had the highest ADCC magnitude, the lowest IgA levels and the highest IgG/IgA ratio, all compared to CT. Positive correlations between CD4(+) T-cell counts and both IgG/IgA ratios and %ADCC killing uniquely distinguished HIV(+)-P. Additionally, evidence of IgA interference with ADCC responses from HIV(+)-P and CT is provided. These data suggest for the first time a potential role of ADCC and/or gp120-specific IgG/IgA balance in modulating heterosexual transmission. In sum, this study provides key information to understand the host factors that influence viral transmission, which should be considered in both the development of prophylactic vaccines and novel immunotherapies for HIV-1 infection.
... Three factors have been proposed to explain the resistance of HEPSN individuals to HIV-1: T cells, elevated numbers of NK cells, and mucosal IgA responses to HIV-1 (120). Some studies have found HIV-specific circulating T cell responses in the peripheral blood of HEPSN individuals (121)(122)(123)(124)(125): Healthcare workers that have been repeatedly exposed to HIV via needle sticks develop robust CD8 (123) and CD4 T cell responses to HIV, without detectable Ab responses (122). In a study of 12 potentially exposed but uninfected men who have sex with men, 4 had a detectable CD8 T cell response to gag and vif (121). ...
Mucosal surfaces provide a remarkably effective barrier against potentially dangerous pathogens. Therefore, enhancing mucosal immunity through vaccines-strengthening that first line of defense-holds significant promise for reducing the burden of viral diseases. The large and varied class of viral pathogens, however, continues to present thorny challenges to vaccine development. Two primary difficulties exist: Viruses exhibit a stunning diversity of strategies for evading the host immune response, and even when we understand the nature of effective immune protection against a given virus, eliciting that protection is technically challenging. Only a few mucosal vaccines have surmounted these obstacles thus far. Recent developments, however, could greatly improve vaccine design. In this review, we first sketch out our understanding of mucosal immunity and then compare the herpes simplex virus, human immunodeficiency virus, and influenza virus to illustrate the distinct challenges of developing successful vaccines and to outline potential solutions.
... Combining humoral and cytotoxic responses in this way may be especially relevant for HIV given associations of high circulating levels of HIV-1-specific cytotoxic T-lymphocytes (CTLs) in long-term non-progressors [279,280] and HIV-exposed seronegative subjects [281]. ...
A combination of advances spanning from isolation to delivery of potent HIV-specific antibodies have begun to revolutionize understandings of antibody-mediated antiviral activity. As a result, the set of broadly neutralizing and highly protective antibodies have grown in number, diversity, potency, and breadth of viral recognition and neutralization. These antibodies are now being further enhanced by rational engineering of their anti-HIV activities and coupled to cutting edge gene delivery and strategies to optimize their pharmacokinetics and biodistribution. As a result, the prospects for clinical use of HIV-specific antibodies to treat, clear, and prevent HIV infection are gaining momentum. Here we discuss the diverse methods whereby antibodies are being optimized for neutralization potency and breadth, biodistribution, pharmacokinetics, and effector function with the aim of revolutionizing HIV treatment and prevention options.
... In support of this are reports of naturally induced T-cell responses specific for gp120 described in cohorts of HIV-1 exposed but persistently seronegative individuals, both from sexual and occupational HIV-1 exposure. [8][9][10][11] We hypothesized that gp120-specific CD8 + T-cell responses, quantitatively or qualitatively, would be associated with infection risk among comparably exposed placebo-treated individuals in the global Pre-exposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial. 12 ...
Association of HIV-1-specific T cell responses to infection risk in seronegative individuals is controversial. We quantified and phenotypically characterized gp120-specific T cell responses in HIV-1-exposed but uninfected subjects enrolled in the global Preexposure Prophylaxis Initiative (iPrEx) chemoprophylaxis trial. IFNγ ELISpot responses were detected in 24% of subjects irrespective of infection outcome. HIV-1 gp120 Envelope-specific T cell responses were more uniformly IFN-γ+TNF-α+Mip-1β+ in persistently seronegative subjects relative to subjects who later seroconverted (median frequency of 76.5% and 66.5%, respectively). IFNγ responses targeted the V2 loop for subjects who remained seronegative. HIV-1 gp120 Envelope V2 loop specific CD8+ T cell responses may help to protect against HIV-1 acquisition.
... The description of HIV-1 exposed individuals that remain sero-negative (HESN) despite repeated high-risk exposure has heightened interest in identifying potential immunemediated mechanisms of protection from HIV-1. HIV-specific humoral and T cell mediated responses were originally identified in a subset of HESN subjects [1][2][3][4][5][6], although the magnitude was significantly lower than comparable responses observed in HIV-1 infected individuals [7,8] and apparently not protective in persistently exposed HESN subjects that later sero-convert [9][10][11]. Decreased CD4 + T cell activation has been suggested as another correlate of protection from infection [12][13][14] as have soluble cytokines and anti-HIV peptides [15][16][17][18][19]. ...
Previous studies have described increased innate immune activation in HIV-1 exposed, sero-negative intra-venous drug users (HESN-IDU), but have not addressed the independent role of injected drugs and/or repeated injections in driving immune activation.
Here, we investigated innate (NK cells and dendritic cells) and adaptive (HIV-specific antibody and CD8 T cell) immune parameters among a high-risk cohort of needle-sharing HESN-IDU subjects and compared them to low-risk non-sharing IDU subjects (NS-IDU) and non drug-user controls.
We observed that HIV-specific antibody and CD8 T cell responses were not detected in HESN-IDU subjects, yet innate immune cell activation was found to be significantly increased on NK cells (CD69 and CD107a upregulation) and MDCs (CD40 and CD83 upregulation) when compared to NS-IDU subjects or non drug-user controls (p<0.01, and p<0.05, respectively). HESN-IDU subjects maintained strong NK cell CD107a degranulation and cytokine (IFN-gamma, TNF-alpha and MIP-1 beta) production following target cell-incubation suggesting that constitutive innate activation does not induce functional exhaustion of innate cells in HESN-IDU subjects. NK activation in HESN-IDU subjects was independent of drug use patterns but was durable over time and correlated with plasma levels of IP-10 by Luminex analysis (rho=0.5073, p=0.0059, n=28).
Our results indicate that heightened innate immune cell activation in HESN-IDU subjects is not the result of the IV-drugs and repeated injection practice itself, but to repeated exposure to factors intrinsic to sharing needles (i.e., exposure to pathogens or heterologous cells among donor blood).
... There is evidence, though, that exposures to HIV-1 that fail to establish infection can still exert immunological effects. For example, HIV-1-specific T cells have been detected in highly HIV-1-exposed individuals who remain seronegative [3][4][5][6][7][8][9][10][11][12][13]. Some studies have also found mucosal HIV-1-specific neutralizing IgA in the cervicovaginal lavage and seminal fluid of HIV-1-negative individuals with HIV-1-infected partners [11,[14][15][16][17]. ...
Background
Many participants in microbicide trials remain uninfected despite ongoing exposure to HIV-1. Determining the emergence and nature of mucosal HIV-specific immune responses in such women is important, since these responses may contribute to protection and could provide insight for the rational design of HIV-1 vaccines.
Methods and Findings
We first conducted a pilot study to compare three sampling devices (Dacron swabs, flocked nylon swabs and Merocel sponges) for detection of HIV-1-specific IgG and IgA antibodies in vaginal secretions. IgG antibodies from HIV-1-positive women reacted broadly across the full panel of eight HIV-1 envelope (Env) antigens tested, whereas IgA antibodies only reacted to the gp41 subunit. No Env-reactive antibodies were detected in the HIV-negative women. The three sampling devices yielded equal HIV-1-specific antibody titers, as well as total IgG and IgA concentrations. We then tested vaginal Dacron swabs archived from 57 HIV seronegative women who participated in a microbicide efficacy trial in Southern Africa (HPTN 035). We detected vaginal IgA antibodies directed at HIV-1 Env gp120/gp140 in six of these women, and at gp41 in another three women, but did not detect Env-specific IgG antibodies in any women.
Conclusion
Vaginal secretions of HIV-1 infected women contained IgG reactivity to a broad range of Env antigens and IgA reactivity to gp41. In contrast, Env-binding antibodies in the vaginal secretions of HIV-1 uninfected women participating in the microbicide trial were restricted to the IgA subtype and were mostly directed at HIV-1 gp120/gp140.
