Continuing the recent theme of covering issues raised by the Merck HIV vaccine trial results, one longstanding concern with T cell-based vaccines is that they might create more CD4 T cell targets for HIV infection. HIV has a well-described proclivity for activated, dividing CD4 T cells, as is evinced by studies showing that CD4 T cell activation by licensed vaccines and co-infections can often lead to a transient increase in viral load in HIV-infected individuals.
Immunization of an HIV-negative person with a T cell-based HIV vaccine creates a pool of “memory” CD4 and CD8 T cells that specifically recognize the HIV components included in the vaccine. If that individual is subsequently exposed to HIV, the HIV-specific CD4 T cells will respond by becoming activated. On one hand, this is a good thing in that these CD4 T cells help initiate an immune response by assisting HIV-specific CD8 T cells in their efforts to kill virus-infected cells and by signaling to B cells to make antibodies. On the other hand, these activated HIV-specific CD4 T cells also represent ideal targets for the virus and some proportion will inevitably become infected. One grim possibility is that infection of even a small proportion of the HIV-specific memory CD4 T cell response could be enough to compromise the overall immune response to HIV, rendering vaccination useless.
However, in the absence of memory CD4 T cells targeting HIV, the first-responders in a person exposed to HIV are naïve (inexperienced) CD4 T cells that recognize the virus. Naïve CD4 T cells have to become activated and undergo multiple divisions in order to develop into memory CD4 T cells, and the few studies that have looked at this issue have found that activated naïve CD4 T cells are even more susceptible to HIV infection than activated memory CD4 T cells. Furthermore, a recent study found that developing memory CD4 T cells are preferentially infected with HIV during acute infection. These findings, although very limited, suggest that having vaccine-induced memory CD4 T cells on board prior to exposure might confer an advantage. Additionally, particular types of memory CD4 T cell may be less susceptible to infection than others; recently presented data has shown that CMV-specific memory CD4 T cells that make the chemokine MIP-1alpha resist HIV infection significantly better than memory CD4 T cells that do not.
The only study to look closely at this issue in the SIV model was published last year in the Journal of Experimental Medicine. Joseph Mattapallil and colleagues studied macaques that were immunized with a DNA prime/adenovirus vector boost regimen encoding SIVmac239 Env and a Gag-Pol fusion protein. Animals were challenged with SIVmac251(an uncloned virus with similar virulence to SIVmac239) a month after their last booster immunization. Post-infection viral loads were significantly lower in vaccinated animals (by approximately 1 log) compared to controls and vaccination was also associated with a relative preservation of gut CD4 T cells (controls lost 50-80% of this CD4 T cell population, vaccine recipients 5-20%). Mattapallil and colleagues specifically evaluated the extent to which SIV infected SIV-specific CD4 T cells; in both vaccine recipients and controls, SIV-specific CD4 T cells were preferentially infected to a similar extent (containing ~2-fold more SIV DNA than CD4 T cells of other specificities). The only difference was that the preferential infection of SIV-specific CD4 T cells was detectable a few days earlier in vaccinated macaques. The researchers conclude that the infection of SIV-specific CD4 T cells did not abrogate the virological and immunological benefits of vaccination in this study.
At worst, the Merck results could indicate that these findings in the macaque/SIV model do not translate to HIV-infected people, and that the susceptibility of CD4 T cells to HIV infection is an Achilles heel for all vaccination approaches. Among the less pessimistic possibilities, it could be the case that the vaccine-induced memory CD4 T cells were overly susceptible to HIV infection either because of their activation state at the time of exposure (see prior post on resting vs, activated memory T cells) or because they lacked the ability to make potentially protective substances like MIP-1alpha. The breadth of the memory CD4 T cell response could also come into play; Merck's vaccine induces responses only to Gag, Pol and Nef, meaning naive CD4 T cells would be responsible for responding to the HIV proteins not included in the vaccine (Env, Tat, Rev, Vif, Vpu and Vpr). This issue of HIV infection of virus-specific CD4 T cell responses is among the many that will need to be explored as the Merck results are investigated in detail.
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