Immune Activation and AIDS Pathogenesis

Donald L Sodora; Guido Silvestri

Disclosures

AIDS. 2008;22(4):439-446. 

In This Article

What causes immune activation in HIV infection?

While there is a broad consensus among investigators that immune activation plays an important role in AIDS pathogenesis, much debate remains as to what causes the HIV-associated immune activation. Many in the field now accept the idea that this phenomenon is multifactorial in nature. We have compiled a list of potential factors that are most likely to contribute to the chronic, generalized immune activation observed during pathogenic HIV or SIV infection ( Table 1 ). The first is the direct effect of HIV on T cells. HIV might directly influence immune activation through binding of the envelope protein gp120/160 to CD4 and/or CCR5, resulting in intracellular signaling;[53,54,55] or through the ability (or lack thereof) of HIVnef to down-modulate the expression of CD3-T cell receptor (TCR) in the infected cells.[56] The second factor capable of inducing systemic immune activation is the host immune response to HIV/SIV. This activation is likely to be initiated at the level of innate immunity - particularly involving plasmacytoid dendritic cells through Toll-like receptor (TLR) stimulation[57,58] - resulting in the activation of adaptive HIV-specific immune responses (humoral and cellular). The role of the virus-specific adaptive immune response (and, most notably, the HIV-specific cytotoxic T-cell response) is particularly complex due to its dual nature, i.e., beneficial as it may suppress virus replication, but harmful as it fuels chronic T-cell activation once the virus has escaped the immune response. Third, it was recently proposed that the HIV-associated immune activation is caused in part by translocation of microbial products from the intestinal lumen to the systemic circulation, where they can activate the immune system by binding to certain TLR (i.e., TLR-2, 4, 5, 6).[48,49] This model postulates that microbial translocation (of which plasma levels of lipopolysaccahride is a reliable marker) occurs as a result of the depletion of intestinal lamina propria CD4 T cells and monocyte/macrophages through to direct cytopathic effect of the virus. It is also important to note that other pathogens, including but not limited to those causing OI during the later stages of disease, might also be playing roles in the HIV-associated immune activation.[59,60,61] For example, helminth infections may result in a more rapid progression to AIDS, possibly by augmenting the level of activation of the immune system.[60] A fourth potential factor is the non-antigen specific bystander activation of T and B lymphocytes caused by increased production of pro-inflammatory cytokines (e.g., tumor necrosis factor-a, IL-1, and others). This production, in turn, is also induced at the level of innate immune response to the HIV/SIV replication and is mediated by various types of accessory cells that are chronically activated. While the mechanisms of this 'bystander' activation are still relatively obscure, it is possible that they also involve the up-regulation of apoptosis related molecules (CD95, TRAIL, DR4/5) on the surface of T cells, thus making them prone to activation-induced cell death.[28,29,30,31,32,54,62] The last potential factor is the depletion and/or dysfunction of CD4 regulatory T cells (Treg) that normally suppress immune activation via mechanisms involving direct cell-to-cell contact, production of cytokines, and inhibition of dendritic cell activity. The role of Treg in HIV and SIV infection has been the subject of intense study over the past few years.[63,64,65,66,67,68,69,70,71,72,73,74,75,76] Conceivably, Treg may play a dual role in HIV/SIV infection, i.e., protective if suppressing the chronic immune activation but harmful if attenuating effective T-cell responses. This dual role of Treg, together with the fact that these cells appear to work in a tissue-specific manner, makes it difficult to interpret correlations between their number and functional state in blood samples and HIV disease progression.

Two still unanswered questions are: (i) why HIV infected individuals fail to effectively control the level of immune activation, as do natural host species infected with SIV, and (ii) why does the excessive activation not resolve as it does in other chronic viral infections (e.g., hepatitis C virus, hepatitis B virus). While the comparison with these may not be altogether appropriate as these viruses do not preferentially infect immune system cells, the case of non-pathogenic SIV infection of African monkey species is particular intriguing as these infections are strikingly similar to pathogenic HIV/SIV infections in terms of the level of virus replication, target cell tropism, and ineffectiveness of antiviral immune responses.[50,51,77]

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