Received Date: January 12, 2015; Accepted Date: January 15, 2015; Published Date: January 22, 2015
Citation: Bharaj P, Chahar HS (2015) Immune Activation in HIV Infection: Friend or Foe. J Antivir Antiretrovir 7:XLVI-XLVII. doi: 10.4172/jaa.1000e123
Copyright: © 2015 Bharaj P, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Nearly 35 million people all over the world are infected with Human Immunodeficiency Virus (HIV) and around 2 million people get infected with the virus each year and the pandemic continues to devastate despite three decades of our understanding of the pathogenesis . Several immunological features play a crucial role in causing progression to AIDS of which chronic immune activation is the most prominent reason [2,3]. It is characterized by increased proinflammatory cytokines; increased expression of T cell activation or exhaustion markers like CD38 and HLA-DR, Programmed Death-1 (PD-1), Tim-3, CTLA-4 and newly described immune regulator PD-1 Homologue (PD-1H) that may interfere with on-going HIV specific cell responses [4-7]. It is now believed that levels of chronic immune activation predict the progression to AIDS independently from viral loads or CD4+ T lymphocyte counts. Both HIV and Simian Immunodeficiency Virus (SIV) infections of natural hosts are associated with loss of integrity of the mucosal barrier in the intestine leading to translocation of microbial products like Lipopolysaccharide (LPS) and flagellins into the circulation .
Immune activation is a natural response by a body during an infection that eventually gets resolved itself to prevent immunemediated pathology and exhaustion. However, in case of HIV infection, the virus persists indefinitely and in response the body maintains its state of immune activation. Once the viral loads are brought under control, immune activation decreases dramatically but residual virus provides a constant trigger to the immune system and low-level activation persists. A potential mechanism contributing to chronic immune activation is the mucosal immune dysfunction demonstrated by severe and rapid depletion of CD4+ T cells from the gut associated with loss of intestinal epithelial cells, disruption of tight junctions, and compromised integrity of the mucosal intestinal barrier that resulted in a significant increase in bacterial components, including Lipopolysaccharide (LPS), flagellin, peptidoglycan, and bacterial CpG-rich DNA domains that are recognized by Toll Like Receptor (TLR) 2, 5, and 9 respectively and 16s DNA in the blood [8,9]. Through the stimulation of TLRs, these bacterial products may also induce pro-inflammatory cytokine production such as TNF-α, IL-6, IL-8, IL-1β and type I interferons . In addition, HIV virus particles themselves are the prime cause of immune activation that activate TLRs and lead to release of pro-inflammatory cytokines like IFN-α, IL-6, IL-8, macrophage inflammatory protein (MIP)-1a, adhesion molecules like ICAM and VCAM. As CD4+ T cells are the prime targets for HIV/SIV infection, perturbations in their subsets like Th17 and Tregs [11,12], memory cells  and T-follicular (Tfh) helper cells  should be pursued as targets to control immune activation.
In addition to immune activation, another feature of chronic HIV-1 infection is ‘immune exhaustion’ which is characterized by the loss of T cell effector functions, up regulation of regulatory markers like PD-1, Tim-3, CD160, CTLA-4 on both CD4 and CD8+ T cells [4-6]. Blocking of negative regulatory molecules like PD-1 has received considerable attention due to partial restoration of immune functions upon modulation of these receptors . Recently a new member of PD-1 family called PD-1 Homologue (PD-1H) was implicated to play an important role in pro inflammatory cytokine secretion and enhancing immune responses to HIV antigens .
Targeting chronic immune activation is of prime importance in optimizing HIV infection in humans. Although ART has achieved reduction in immune activation to significantly lower levels with successful control of viremia, the immune activation never returns to the baseline like uninfected controls. Alternative drug therapies like co administration of cyclosporine A with combination ART may inhibit T cell activation, proliferation and effector functions by inhibiting gene expression of pro-inflammatory cytokines like IL-2, IL-4, TNF-α and upregulates TGF-β an immune suppressive cytokine . Among other classes of tested agents include chloroquine that showed significant promise in reducing HIV viral loads in ART naïve patients without the patients developing drug resistance . Administering exogenous cytokines like IL-7 has been shown to restore naïve and memory CD4+ T cell function . Certain other compounds like rapamycin and mycophenolic acid may help as additive therapy in conjunction with ART in HIV infected patients by reducing T cell proliferation and activation, thus reducing available targets for HIV replication and viral loads as well [18,19].
In conclusion, HIV causes progressive impairment of the immune system in humans and 30 years after its discovery, its role to the exhaustion of immune system are still incompletely understood. Generalized immune activation associated with HIV infection has become the major driving force behind perturbations of the immune system and predictor of progression to AIDS. Both viral and host factors contribute to this phenomenon and the lack of patho-physiological mechanisms causing this is negatively impacting our ability to improve patient lifestyle. This review highlights the benefits associated by targeting immune activation to reduce disease progression and non- AIDS related pathological side effects on HIV induced chronic immune activation.