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Posted: 20 Oct 2011
30 years in 30 weeks, 2005

The strengths of the non-human primate model in discovering the important details of HIV pathogenesis shine in the study of Roederer et al., who looked at multiple compartments in macaques acutely infected with SIV and found drastic losses of CD4 memory cells throughout the body within days after infection. Preventing this early damage to the immune system can be critical for prolonging the time between infection and AIDS.

Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection.
Nature. 2005 Apr 28;434(7037):1093-7.
Mattapalli JJ, Douek DC, Hill B, Nishimura Y, Martin M, Roederer M.

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Commentary by Drs. Mattapallil and Roederer

223
Dr. Mario Roederer
Until the early 2000’s, HIV infection was thought to be a slow disease characterized by immunodeficiency resulting from a progressive depletion of CD4 T cells. Because of the very low rate of infection of these cells by HIV (typically <0.1%), the selective depletion was thought to occur primarily by bystander mechanisms rather than viral cytolysis.  Moreover, the gut mucosa, replete with highly activated CD4 T cells, was proposed to be the hotbed of acute viral replication and immunopathogenesis; observations suggested that CD4 depletion during acute infection was restricted to the mucosal tissues.

We set out to characterize viral dynamics and immunopathogenesis throughout the body in the nonhuman primate (NHP) model of HIV infection (SIV).  Using detailed characterization of multiple CD4 T cell subsets, we found that acute immunopathogenesis was not restricted to the gut, but was equal in magnitude throughout the entire body when focusing in on memory CD4 T cells, the primary target for HIV/SIV.  Furthermore, we discovered this body-wide depletion of memory CD4 T cells could be accounted for solely by viral infection and cytolysis: that the acute infection was a raging storm of viral replication that infected and destroyed upwards of 80% of the memory compartment – orders of magnitude greater than previously thought.

Our study was driven by the evaluation of the heterogeneity of the immune system.  Mucosal CD4 T cells are relatively homogenous in nature with a predominantly activated memory phenotype, whereas CD4 T cells in peripheral tissues are a heterogeneous mix of naïve, resting memory, and activated memory CD4 T cells.  This latter mixture largely masks the destructive nature of HIV in the periphery and blood, since naïve T cells (~50%) remain unaffected during acute HIV/SIV infection. Importantly, we found that memory CD4 T cells in the periphery were being lost at the same rate as that of the mucosal CD4 T cells – demonstrating that acute immunopathogenesis is not solely a mucosal (nor gut) phenomenon, but rather that up to 80% of all memory CD4 T cells in the body would be destroyed during the first four weeks following infection.  The manifestation of this destruction in the gut is a near-total depletion of CD4 T cells, because the gut CD4 compartment is essentially 100% memory T cells.

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Dr. Joseph M. Mattapallil
We also sought to determine the mechanism for this massive destruction; we reasoned that if virus was responsible, then memory T cells at these early times should have detectable, integrated viral DNA. With our collaborators, we developed a quantitative assay to determine the level of SIV DNA in purified populations of naïve and various memory CD4 T cells isolated from different tissues during acute infection. To our surprise, we found enormous amounts of SIV DNA in memory CD4 T cells even at day 10: an average of 1-2 viral genomes per memory CD4 cell.  Since very few cells were infected only 3 days earlier, there is a massive explosion of cellular infection after the first week. 

From days 10 to 14, the SIV DNA level decreased more than 50%.  This could have been due to loss of few cells that were heavily superinfected or a large number of cells that were all infected. By quantifying SIV at the single cell level, we found that each infected memory CD4 T cell harbored ~1-2 copies of SIV DNA, suggesting that the loss of viral DNA was explained by the commensurate loss of CD4 memory T cells observed phenotypically. These findings for the first time provided a clear mechanism for the loss of memory CD4 T cells in both mucosal and peripheral tissues, and showed that the loss was systemic and massive.  Our data also ruled out the need to invoke any uncharacterized “bystander” killing of CD4 T cells.

The study was enormously challenging – the extensive sampling of multiple tissue compartments, detailed immunophenotyping and molecular analysis, and coordination of the infection of NHP was complex.  It is also a testament to the power of the NHP model; similarly comprehensive studies in man are impossible.  Nonetheless, confirmation of many aspects of our findings in clinical specimens has come from a number of studies of recently infected adults.

Perhaps the most significant hypothesis arising from these studies was that protection from this acute immunopathogenesis would provide a significant health and survival benefit.  Strong evidence for this came from NHP T cell vaccine studies, in which it was demonstrated that vaccine-mediated amelioration of acute phase CD4 destruction correlated with a significantly longer life span.  This suggests that while protection against infection remains paramount in HIV vaccine development, the elicitation of strong cellular responses may provide a significant benefit in those subjects who still become infected.

Finally, it should be noted that this study was performed using intravenous viral challenge.  Very recent studies in our laboratory suggest that mucosal challenge results in a milder acute depletion of cells; however, the acute immunopathogenesis is still dramatic and sets the stage for the progressive immunodeficiency that is the hallmark of AIDS.  Indeed, a large retrospective clinical study we carried out on samples 470 HIV-infected adults showed that the level of infection of CD4 cells measured within 9 months of infection was a very powerful predictor of subsequent progression.  Thus, in both NHP and humans, the destruction occurring during acute/early infection is a critical factor in determining long-term outcome. 

About the authors:
Joseph M. Mattapallil is an Assistant Professor at the Department of Microbiology and Immunology at the Uniformed Services University

Mario Roederer is the Chief of the ImmunoTechnology Section in the Laboratory of Immunology at the Vaccine Research Center

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