HIV-induced Immune Activation Research Articles

Immune profiling in Puerto Rican injection drug users with and without HIV-1 infection.

Antiretroviral therapy has been effective in suppressing HIV viral load and enabling people living with HIV to experience longer, more conventional lives. However, as people living with HIV are living longer, they are developing aging-related diseases prematurely and are more susceptible to comorbidities that have been linked to chronic inflammation. Coincident with HIV infection and aging, drug abuse has also been independently associated with gut dysbiosis, microbial translocation, and inflammation. Here, we hypothesized that injection drug use would exacerbate HIV-induced immune activation and inflammation, thereby intensifying immune dysfunction. We recruited 50 individuals not using injection drugs (36/50 HIV+) and 47 people who inject drugs (PWID, 12/47 HIV+). All but 3 of the HIV+ subjects were on antiretroviral therapy. Plasma immune profiles were characterized by immunoproteomics, and cellular immunophenotypes were assessed using mass cytometry. The immune profiles of HIV+/PWID-, HIV-/PWID+, and HIV+/PWID+ were each significantly different from controls; however, few differences between these groups were detected, and only 3 inflammatory mediators and 2 immune cell populations demonstrated a combinatorial effect of injection drug use and HIV infection. In conclusion, a comprehensive analysis of inflammatory mediators and cell immunophenotypes revealed remarkably similar patterns of immune dysfunction in HIV-infected individuals and in people who inject drugs with and without HIV-1 infection.

Peripheral Vγ9Vδ2 T Cells Are a Novel Reservoir of Latent HIV Infection

Eradication of HIV infection will require the identification of all cellular reservoirs that harbor latent infection. Despite low or lack of CD4 receptor expression on Vδ2 T cells, infection of these cells has previously been reported. We found that upregulation of the CD4 receptor may render primary Vδ2 cells target for HIV infection in vitro and we propose that HIV-induced immune activation may allow infection of γδ T cells in vivo. We assessed the presence of latent HIV infection by measurements of DNA and outgrowth assays within Vδ2 cells in 18 aviremic patients on long-standing antiretroviral therapy. In 14 patients we recovered latent but replication-competent HIV from highly purified Vδ2 cells demonstrating that peripheral Vδ2 T cells are a previously unrecognized reservoir in which latent HIV infection is unexpectedly frequent.

HIV and the heart: the impact of antiretroviral therapy: a global perspective

From a global perspective, cardiovascular disease (CVD) in human immunodeficiency virus (HIV) may result from cardiac involvement upon presentation of opportunistic infections in the presence of advanced immunosuppression, be a consequence of HIV-induced immune activation or derive from antiretroviral therapy-associated dyslipidaemia and insulin resistance. Indeed, in developed countries with unlimited access to antiretroviral therapy CVD has become one of the major causes of death in HIV. Therefore, cardiovascular risk reduction and lifestyle modifications are essential and careful selection of the antiretroviral drugs according to underlying cardiovascular risk factors of great importance. In developing countries with delayed roll-out of antiretroviral therapy pericardial disease (often related to TB), HIV-associated cardiomyopathy, and HIV-associated pulmonary hypertension are the most common cardiac manifestations in HIV. In Africa, the epicentre of the HIV epidemic, dynamic socio-economic and lifestyle factors characteristic of epidemiological transition appear to have positioned the urban African community at the cross-roads between historically prevalent and 'new' forms of CVD, such as coronary artery disease. In this context, cardiovascular risk assessment of HIV-infected patients will become a critical element of care in developing countries similar to the developed world, and access to antiretroviral therapy with little or no impact on lipid and glucose metabolism of importance to reduce CVD in HIV.

Drug-Resistant Virus Has Reduced Ability to Induce Immune Activation

There is increasing suspicion that HIV-induced immune activation contributes to accelerated cellular turnover, CD4+ T-cell losses and increased morbidity and mortality of HIV-infected individuals, even for those on antiretroviral treatment 1,2,3,4. For example, Kuller et al.5 found that higher levels of interleukin-6 (IL-6) were significantly associated with an increased risk of all-cause mortality; similar associations with mortality were seen for higher levels of d-dimer and hsCRP. Deeks et al.6 have hypothesized that the preserved immunologic function in many treated patients with drug-resistant viremia is the result of a reduction in T cell activation. Hunt et al.7 reported that antiretroviral-treated patients with drug-resistant viremia have lower T cell activation than untreated patients, controlling for plasma HIV-1 RNA level. Kitchen et al.8 reported an oscillatory relationship between T cell activation, CD4 T cell counts and HIV-1 RNA levels over time in a group of subjects with highly resistant HIV infection followed longitudinally.

Inhibitory effects of chloroquine on the activation of plasmacytoid dendritic cells in SIVmac239-infected Chinese rhesus macaques

It is currently widely accepted that immune activation in HIV-infected individuals leads to a severe loss of CD4⁺ T cells and the progression to AIDS. However, the underlying mechanism of this immune activation remains unclear. Experimental data suggest that the activation of plasmacytoid dendritic cells (pDCs) by plasma viremia may play a critical role in HIV-induced immune activation. In this study, we found that the level of immune activation was higher in the late phase of SIVmac239 infection compared with chronic infection, which suggests that immune activation might be related to disease progression in SIVmac239-infected non-human primate models. Our work also showed that chloroquine could effectively inhibit the activation of pDCs in vitro and in vivo. However, chloroquine treatment of SIVmac239-infected macaques had no significant influence on the Cellular composition of peripheral blood in these animals.

The CD8+ HLA-DR+ T cells expanded in HIV-1 infection are qualitatively identical to those from healthy controls.

HIV-induced immune activation leads to expansion of a subset of human CD8(+) T cells expressing HLA-DR antigens. Expansion of CD8(+) HLA-DR(+) T cells can be also observed in non-HIV settings including several autoimmune diseases and aging. Although these cells are felt to represent "immune exhaustion" and/or to be anergic, their precise role in host defense has remained unclear. Here, we report that this subset of cells exhibits a restricted repertoire, shows evidence of multiple rounds of division, but lacks markers of recent TCR engagement. Detailed cell cycle analysis revealed that compared with their CD8(+) HLA-DR(-) counterpart, the CD8(+) HLA-DR(+) T-cell pool contained an increased fraction of cells in S-phase with elevated levels of the G2/M regulators: cyclin A2, CDC25C, Cdc2 (CDK1), indicating that these cells are not truly anergic but rather experiencing proliferation in vivo. Together, these data support a hypothesis that antigen stimulation leads to the initial expansion of a CD8(+) pool of cells in vivo that undergo further expansion independent of ongoing TCR engagement. No qualitative differences were noted between CD8(+) HLA-DR(+) cells from HIV(+) and HIV(-) donors, indicating that the generation of CD8(+) HLA-DR(+) T cells is a part of normal immune regulation that is exaggerated in the setting of HIV-1 infection.

Humanized mice as a useful model to study HIV-1 induced immune activation, its mechanisms and potential therapeutic approaches

Recent understanding of HIV-1 pathogenesis mechanism has changed our views about possible mechanisms of CD4T-cell depletion during infection. Apart from HIV-1-mediated killing a more comprehensive explanation has appeared that includes T cell exhaustion and chronic immune activation as a central feature in HIV-1 pathogenesis. While highly active antiretroviral therapy (HAART) markedly reduces viral load, T cell activation levels and soluble markers of inflammation remain abnormally high. Markers of chronic activation, such as CD38, PD-1 or HLA-DR on T cells, appear to be better predictors for clinical progression during HIV infection than HIV RNA levels and CD4Tcell counts alone. Therefore, a better understanding of HIV-induced immune activation and the design of new immunomodulatory approches in combination with HAART are needed. We have generated an efficient model of human stem cells (HSCs) engraftment in NOD/LtsZ-scidlL-2Rnull (NSG) mice that supports chronic HIV infection with high plasma viral loads. HIV-1 infection in these humanized mice is characterized by widespread immune activation with increased expression of PD-1, HLA-DR, CD38, CD69, CD25 and other immune activation markers. These humanized mice provide an effective in vivo system for the assessing novel approaches for their potential in suppressing chronic immune activation during HIV-1 infection, in absence of interference of antiretroviral therapy. In this study, we evaluated in vivo the benefits of two novel approaches aimed at reducing HIV-induced immune activation. Minocycline is an antibiotic of the tetracycline family with anti-inflammatory and immunomodulatory properties affecting CD4 T cells activation by a mechanism involving the inhibition of the NF-AT1 transcription factor activity. We hypothesized that this antibiotic could suppress the HIV-1-induced chronic immune activation and thus, limit the HIV pathogenesis when combined to HAART. Therefore, we treated HIV-1 (JRCSF) infected-humanized NSG mice with minocycline (100mg/kg/day) for 60 days. We next evaluated the expression, by flow cytometry, of several T cells activation markers together with CD4+T cells counts. Our data suggest that minocycline is effective in suppressing HIV-1 induced immune activation in peripheral blood and lymphoid organs (spleen, lymph nodes and bone marrow). Levels of cellular immune activation markers such as PD-1, HLA-DR, CD38, CD69, CD25, CD28 and CTLA-4 were significantly lower in minocycline treated group. These immunological benefits of minocycline were correlated with higher CD4+T cell counts in the treated group. The immune activation which is associated with retroviral infection is also associated with increased levels of intracytoplasmic cyclic AMP which could act as a positive feedback loop in the infection since several reports have suggested that cAMP and downstream signaling pathways play an important role in the permissivity of susceptible cells to HIV infection and replication. We have used a peptide which prevents the binding of the catalytic subunit of PKA type I to its anchoring protein and therefore blocks most effects of cyclic AMP within lymphocytes and monocytes (RIAD peptide). Mice were treated with 3.5 mg/kg of RIAD peptide weekly. Treatment of humanized mice with RIAD peptide limited viral replication after high dose of HIV intraperitoneal challenge and reduced the intracytoplasmic levels of cyclic AMP. Further experiments are needed to better appreciate the therapeutic potential of these novel therapies in the suppression of HIV-induced chronic immune activation.

HIV-induced immune activation - pathogenesis and clinical relevance. Summary of a workshop organised by the German AIDs Society (DAIG e.v.) and the ICH Hamburg, Hamburg, Germany, November 22, 2008

This manuscript is communicated by the German AIDS Society (DAIG) http://www.daignet.de. It summarizes a series of presentations and discussions during a workshop on immune activation due to HIV infection. The workshop was held on November 22nd 2008 in Hamburg, Germany. It was organized by the ICH Hamburg under the auspices of the German AIDS Society (DAIG e.V.).

Pathogenesis of HIV: non-specific immune hyperactivity and its implications for vaccines

More than a decade ago, the pathogenesis of AIDS was reviewed in this journal, using the subtitle 'classical and alternative views', when evidence was accumulating that HIV could not cause AIDS simply through direct cytopathic mechanisms alone. Generalised immune activation after infection with HIV is now understood to be associated with and predictive of disease progression and probably represents the single most important difference between rapid progression and slow or non-progression. However, the fundamental source of this phenomenon remains undetermined. Do pathogenic events after acute infection promote an environment susceptible to increased hyperactivity or does inherent reactivity towards HIV in susceptible individuals ultimately influence these processes? New strategies aimed at eliminating HIV-induced immune activation are required, as is investigation into the clinical and immunological influence of antibodies that target HIV epitopes associated with disease and that are not necessarily neutralising. Therapeutic vaccines to prevent disease may be more practical and effective than classic prophylactic vaccination.

Two overrepresented B cell populations in HIV-infected individuals undergo apoptosis by different mechanisms

Perturbations of B cells in HIV-infected individuals are associated with the overrepresentation of distinct B cell populations. Here we describe high extrinsic CD95 ligand (CD95L)-mediated apoptosis in CD10-/CD21lo mature/activated B cells that likely arise from HIV-induced immune activation. In addition, high intrinsic apoptosis was observed in CD10+ immature/transitional B cells that likely arise as a result of HIV-induced lymphopenia. CD10+ B cells expressed low levels of Bcl-2 and Bcl-xL, consistent with their high susceptibility to intrinsic apoptosis. Higher levels of activated Bax and Bak were induced in CD10+ B cells compared with CD95L-treated CD10- B cells, consistent with the greater involvement of mitochondria in intrinsic vs. extrinsic apoptosis. Of interest, both extrinsic apoptosis in CD95L-treated CD10- B cells and intrinsic apoptosis in CD10+ B cells were associated with caspase-8 activation. Our data suggest that two distinct mechanisms of apoptosis are associated with B cells of HIV-infected individuals, and both may contribute to the depletion and dysfunction of B cells in these individuals.

Pathogenic Mechanisms of HIV Disease: The Role of Viral Replication and Immune Activation

HIV replication and the immune response to the virus lead to a state of generalized immune activation, which drives the pathogenesis of HIV disease. HIV-induced immune activation results in increased T-cell turnover (production and destruction), increased death of T cells, a decline in the size of the CD4+ T-cell pool, and a state of activation-induced immunodeficiency. In many HIVinfected individuals, these phenomena can be reversed or mitigated with effective antiretroviral therapy (ART), which blunts HIV replication and can reduce plasma levels of viremia to undetectable levels. Recent data from our laboratory have demonstrated fundamental differences between viremic and aviremic individuals with regard to the physiologic state of the resting CD4+ T-cell reservoir of HIV and the phenotype and function of T cells, B cells and natural killer (NK) cells. In terms of the CD4+ T-cell reservoir, resting cells in viremic versus aviremic individuals differentially express certain genes associated with HIV replication and are continually poised to express virus as a result of continual activation related to viremia; thus, true latency likely does not exist in these patients. We had previously reported that much greater stability exists in aviremic individuals, suggesting the presence of a truly latent reservoir of virus in this population. However, recent data indicate that the normal physiologic process of low-level immune activation in aviremic individuals sustained the low level turnover and propagation of the latent HIV reservoir. Previously, we have demonstrated that HIV-mediated hyperactivation induces the terminal differentiation of B cells. More recently, we have determined that certain B-cell genes are upregulated in HIVviremic individuals as compared with HIV-aviremic individuals. Many of these genes are associated with terminal B-cell differentiation and death by apoptosis. Recent data indicate that there is a balance between expression of survival and apoptotic genes in HIV-infected individuals that is impacted by the presence and level of viremia. In viremic individuals we also have characterized a population of aberrantly activated CD56NK cells that manifest lower-than-normal expression of Natural Cytotoxicity Receptors and a normal or increased expression of inhibitory NK receptors. This dichotomy is reflected in decreased cytotoxic function and decreased secretion of TNF-alpha and interferon-gamma. In addition, NK cells from viremic individuals express Fas on their surfaces at significantly increased levels, and are more susceptible to apoptosis upon exposure to sFASL. Furthermore, viremia impacts the NK cell-dendritic cell interactions that are critical to normal immune responsiveness. Taken together, our data indicate that HIV pathogenesis involves both direct and indirect effects of HIV and a relentless cycle of aberrant immune activation that drives the disease process in HIV-infected individuals. from 2005 International Meeting of The Institute of Human Virology Baltimore, USA, 29 August – 2 September 2005

CD4+ t-cell depletion in hiv infection: Killed by friendly fire?

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.