December 27, 2006

Gag Reflex: HIV Protein Should Be Vaccine Target
(AIDSmeds.com)

An effective immune response against HIV infection may depend on "killer" CD8 cells targeting HIV's Gag protein, a finding that may pave the way for successful vaccine development. The new research, published online as a Nature Medicine pre-press report, comes from a collaborative study conducted by Investigators at Massachusetts General Hospital's Partners AIDS Research Center (PARC), the University of Oxford, and the University of KwaZulu-Natal in South Africa.

Understanding which immune responses are effective in the control of HIV is of critical importance in vaccine development. Previous efforts to develop an effective vaccine embodied a "more is better" approach, seeking to generate responses against a broad range of viral proteins. The new research, reported by Philip Goulder, MD, PhD, of PARC and Oxford, and his colleagues, challenge these earlier assumptions.

Many strategies for developing a vaccine to control HIV have focused on the activity of the CD8 (T8) cells that recognize and destroy HIV-infected CD4 (T4) cells in the body. However, high numbers of CD8 cells are frequently seen in HIV-positive people, including those who progress slowly (or not at all) to AIDS and those who experience typical or rapid disease progression.

To make sense of this, the researchers followed up on earlier studies suggesting that it is the quality of the CD8 cell response to HIV, not the quantity of the response, that matters most. To do this, they enrolled 578 South African HIV-positive people who had not yet received antiretroviral therapy. The study investigators then compared the different types of CD8 cell responses seen in patients with low viral loads in the absence of treatment – a sign of immune system control of infection – with those of patients with higher viral loads.

Dr. Goulder's group "mapped" the CD8 responses against all of HIV's proteins and also investigated whether the versions of human leukocyte antigen (HLA) Class I molecules involved in the immune system's recognition of HIV protein fragments made a difference. When new viruses are produced within an infected CD4 cell, HLA Class I molecules grab viral fragments and display them on the cell's surface, alerting CD8 cells that the cell has been infected and should be destroyed. Earlier studies, including a 2004 published report from the same group, showed that the genetically determined version of an individual's HLA Class I molecules could strongly influence immune control of HIV.

The current study found that CD8 responses against HIV's Gag protein were the only ones associated with good immune system control of HIV infection, indicated by low viral loads in the absence of treatment. The HIV-positive patients with CD8 responses against several different Gag fragments had even lower viral loads.

In contrast, those with stronger responses against other HIV proteins – including Env, a protein that is the focus of several vaccine studies – had higher viral levels indicating poorer control of HIV.

In people receiving no antiretroviral treatment, Dr. Goulder's group concludes, the improved HIV control associated with Gag-specific CD8 response may translate into many years of asymptomatic infection, compared with typical or more rapid progression in those with other CD8 cell responses. In turn, even if a vaccine is unable to prevent HIV infection in those exposed to the virus, it may still be considered successful if it elicits a Gag-specific immune response and, ultimately, keeps viral load low and prolongs survival.

Dr. Goulder and his colleagues caution that the mechanisms underlying the different effects of the protein-specific immune responses are unknown and require further investigation. The findings of this study, involving people with documented HIV infection, might not apply in situations in which vaccination generates an immune response before infection occurs.

Source:

Kieliela P, Ngumbela K, Thobakgale C, et al. CD8+ T-cell responses to different HIV proteins have discordant associations with viral load. Nature Med. Published online: December 17, 2006.