New paradigms for HIV/AIDS vaccine development

Abstract

HIV-1 and its simian counterpart SIV have been exquisitely tailored by evolution to evade host immunity. By virtue of specific adaptations that thwart individual innate or adaptive immune mechanisms, and an overall replication strategy that provides for rapid establishment of a large, systemic viral population, capable of dynamic adaptation to almost all immune selection pressures, these viruses, once established, almost invariably stay one step ahead of the host's immune system, and in the vast majority of infected individuals, replicate indefinitely. Although many vaccine approaches tested to date have been able to enhance the magnitude of the immune responses to HIV/SIV infection, most of these responses, whether cellular or humoral, have largely failed to be both effectively antiviral and targeted to prevent the emergence of fully functional escape variants. Recent advances, however, have provided strong evidence that the initial stages of infection following mucosal transmission of these viruses are more vulnerable to immune intervention, and have led to the development of vaccine strategies that elicit responses able to effectively intervene in these early stages of infection, either preventing acquisition of infection or establishing early, stringent, and durable control. Here, we place HIV/AIDS vaccine development in the context of the basic immunobiology of HIV and SIV, review the evidence for their vulnerability to immune responses immediately after mucosal transmission, and discuss how this newly recognized vulnerability might be exploited for the development of an effective HIV/AIDS vaccine.

Figure 1

Schema of peripheral T cell differentiation. The figure shows the coordinate changes in T cell homing behavior, expansion capacity, and effector function that occur with progressive differentiation in the peripheral immune system. Because of the CCR5 tropism of transmitted strains of HIV/SIV and the preferential expression of CCR5 in later stages of memory differentiation, this differentiation process is fundamental to HIV/SIV immunopathogenesis, providing for selective targeting of later stage (T_EM) CD4+ memory cells while sparing a progenitor population (T_CM) for continued production of new targets. Mechanisms of memory T cell differentiation are equally important to the activity of vaccine-elicited T cell responses as they determine whether such responses predominantly localize in lymphoid tissue and respond to infection with expansion, effector differentiation, and delayed migration to effector sites (T_CM), or in extra-lymphoid effectors sites, allowing immediate interception of transmitted virus in such sites (T_EM).

Figure 2

The typical course of early SIVmac infection and kinetics of T cell response development in unvaccinated Indian-origin rhesus macaques is compared to animals vaccinated with T_CM-generating prime-boost approaches using non-persistent vectors vs. T_EM-generating CMV vectors. Note that only CMV vector-elicited responses can suppress infection during the window of opportunity, and thereby prevent the onset of irreversible, progressive systemic infection.

Figure 3

Stages of early HIV/SIV infection and the point of effective intercept of the designated vaccine approaches.