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Posted: 9 Dec 2011
Targeting the targets of HIV: Is it a good vaccine idea?

In this week's Journal Club, Morgane Rolland contrasts the role of CD4+T cells in establishing HIV-1 infection with recent findings showing that CD4+ T cells might have a key role in the control of viral replication.

CD4+ T cells are the main targets of HIV-1 infection, probably because of that they have only been peripheral in vaccine design strategies.  Recent results showing a role for CD4+ T cells in the control of viral replication may renew interest in CD4+ T cells as crucial intermediaries for the success of an HIV-1 vaccine.  Of course, CD4+ T cells play a key role in sexual transmission of HIV-1: the infection is first established in suboptimally activated memory CD4+ T cells in the genital mucosa, then fully-activated memory CD4+ T cells are recruited leading to high replication levels concurrent with the migration to draining lymph nodes and gut-associated lymphoid tissues (GALT) (Zhang, Schuler et al. 1999; Haase 2010).

A new study from Lyle McKinnon and colleagues in the Journal of Immunology (McKinnon, Nyanga et al. 2011) further describes the key role of CD4+ T cells in the establishment of HIV-1 infection by identifying a subset of CD4+ T cells that expresses several markers of increased susceptibility to HIV.  Cervical Th17 CD4+ T cells with high CCR5, alpha4beta7, and IFN-gamma expression were depleted from the cervix of HIV-1+ women.  These results show that cervical CD4+ T cells are key targets in the HIV-1 transmission process, and they mirror the findings that alpha4beta7+ CD4+ T cells are preferentially infected in the rectal mucosa (Cicala, Martinelli et al. 2009).

It is undeniable that CD4+ T cells are fueling new HIV-1 infections; yet, two new studies, one in humans and one in macaques, lend credence to the hypothesis of CD4+ T cells having a key role in the control of viral replication.

Figure 1. Data from Ranasinghe et al. showing divergent clinical outcomes associated with CD4+  T cell responses targeting different HIV-1 proteins.

Ranasinghe and colleagues (Ranasinghe, Flanders et al. 2011) identified HIV-specific IFNgamma+ CD4+ T cell responses in 93 individuals, including both HIV-1 controllers and progressors (Figure 1).  This comprehensive study using 410 overlapping peptides across the HIV-1 B proteome showed that a higher number of HIV-specific CD4+ T cell responses was associated with lower viral loads, especially if these responses targeted Gag.  Interestingly, they showed that almost all HIV-infected subjects made one or more CD4 response(s), respectively 92% and 89% of individuals.  HIV controllers preferentially targeted Gag, whereas HIV progressors preferentially targeted Env.  Logically, a high ratio of Gag/Env responses predicted viral control.  These findings parallel previous studies of CD8+ T cell responses showing more favorable disease outcomes for people, whose CD8+ T cell responses targeted Gag (Kiepiela, Ngumbela et al. 2007).

Figure 2. Data from Ortiz et al. showing the mean log plasma viral load (A), and survival curves (B) for CD4+ lymphocyte depleted and control rhesus macaques. Setpoint viral loads were significantly higher in treated animals (p = 0.04).

In the SIV model, Ortiz and colleagues (Ortiz, Klatt et al. 2011) showed the profound effect of CD4+ T cells depletion on post-peak viremia in SIV-infected rhesus macaques. CD4+ T lymphocytes were depleted from 5 rhesus macaques, resulting in a 90-95% decrease in CD4+ T cells in blood, lymph nodes and bone marrow, but not in mucosal effector sites.  The depleted and control macaques were infected 45 days later with SIVmac251.  All animals showed comparable peak viral levels, but, in contrast to the control animals, CD4-depleted macaques showed no subsequent decline in viremia and progressed rapidly to AIDS (Figure 2).  Both CD4+ T lymphocyte-depleted and control animals presented systemic CD4+ T cell loss following infection.  The lack of decline in viremia was attributed to the absence of CD4+ T cell-mediated antiviral response, because target cells were not excessively activated and there was no increase in the rate of infection of na├»ve CD4+ T cells.  In addition, CD4+ T lymphocyte-depleted macaques mounted SIV-specific CD8+ T cell responses comparable to those found in control animals; and there was no deficiency in the humoral response.  The authors also presented evidence that viruses from CD4+ T lymphocyte-depleted macaques evolved the ability to enter target cells independent of CD4 receptor (in 4 of 5 animals; none in the control group).

Together, these studies better define the importance of CD4+ T cells in HIV-1 pathogenesis and they have implications for the development of new vaccine strategies as they provide concrete evidence that inducing HIV-specific CD4+ T cells may be critical to mediate a protective antiviral effect.

About the author: Morgane Rolland is a scientist at the US Military HIV Research Program. The views expressed herein do not represent the official views of the US Department of Defense or Department of the Army.

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