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Highly active antiretroviral therapy (HAART) of HIV-infected people results in viral control. When HAART is interrupted, however, HIV-infected individuals lose viral control and show reappearance of plasma viremia. Thus, they need to continue HAART almost forever for prevention of AIDS progression. Cytotoxic T lymphocyte (CTL) responses play an important role in viral suppression but are mostly reduced during HAART. There have been many attempts to develop therapeutic vaccines inducing CTL responses during HAART toward better control, although none of them has yet shown sufficient efficacy.

Development of an effective AIDS vaccine is considered essential for control of HIV pandemic. Previous failures in clinical vaccine trials have indicated the importance of virological and immunological basic studies for elucidation of the mechanism of HIV control. This review describes current progress in prophylactic AIDS vaccine development.

In human immunodeficiency virus (HIV) infections, host immune responses fail to control viral replication and allow persistent HIV infection, resulting in AIDS progression. Analyses in animal AIDS models as well as in HIV-infected individuals are essential for understanding the mechanism of viral replication in vivo and disease progression. HIV-mediated AIDS progression is seen only in humans, and simian immunodeficiency virus (SIV) infection in macaque monkeys is currently considered as the best model for these analyses. Furthermore, studies on replication of HIV, SIV, and HIV-SIV chimeric viruses in humans and macaques may contribute to elucidation of the mechanism for viral tropism.

In the natural courses of human immunodeficiency virus (HIV) infections, host immune responses fail to contain the virus and allow persistent HIV replication, leading to AIDS progression. For development of an effective vaccine against those viral infections which do not show spontaneous remission, it is important to elucidate which immune responses to be induced for viral control. This review focuses on antibodies and cytotoxic T lymphocytes, key adaptive immune effectors, and discusses possible mechanisms for HIV control by vaccine-induced antibody, memory B lymphocyte, and (effector and central) memory T lymphocyte responses. Finally, we mention the ongoing international project for a clinical trial of our Sendai virus vector-based AIDS vaccine.

Despite tremendous efforts to develop HIV vaccines eliciting virus-specific T-cell responses, whether this strategy can really result in HIV control remains unknown. It is important to determine what T-cell responses are responsible for primary HIV control. Recently, encouraging HIV vaccine trials indicated that vaccine induction of highly effective cytotoxic T lymphocytes (CTLs) may result in viral containment in a macaque AIDS model. CTLs exerting strong suppressive effect on viral replication frequently select for escape mutations at the cost of viral fitness. Thus, analysis of CTL-induced viral polymorphisms would contribute to determination of effective CTLs that may be essential for HIV control.

A logical approach for prophylactic HIV-1 vaccine development begins by recognition that the regimen needs to contain viruses which are not cleared by primary host immune responses and develop persistent infection. Hence the required strategy is different from the one against self-remitting acute infections which aims at eliciting robust host immune responses in advance by infection mimicry. Host adaptive immune responses do play a central role in primary resolution from acute HIV-1 and simian immunodeficiency virus (SIV) infection, but as observed in the non-remitting disease course, their function is not fully exerted, leading to failure in viral containment. Either overcoming the limitations of antiviral immunity in natural infection or augmenting the effectors potentially capable of controlling virus replication would be essential for development of an effective HIV-1 vaccine. This approach is hand-in-hand with understanding of the reversibility of various steps leading to establishment of persistent HIV-1 infection. This article reviews the interplay between HIV-1/SIV and the infected host, mainly focusing on macaque models of SIV infection and characterization of the two major wings of adaptive immunity, cytotoxic T lymphocytes (CTLs) and neutralizing antibodies. Discussed in parallel are the up-to-date topics of HIV-1 vaccine development including our recent progress.