HIV Subtype in Thailand Spreads More Easily Through Heterosexual Transmission Than U.S. Subtype

People Infected with Second AIDS Virus Found to Have Natural Protection Against HIV-1

People Infected with HIV-2 Found to Have Longer-Term Survival Than Those Infected with HIV-1

Long-Term Non-Progression Linked To Mutation Profiles of HIV

Finding Has Significant Implications for AIDS Vaccine Development

June 25, 1996 - Harvard AIDS Institute researchers have discovered that the virus found in HIV-infected people with slower disease progression accumulates disproportionately more mutations in a particular region of the viral envelope than that found in people who develop AIDS more quickly. This finding, reported in today's Proceedings of the National Academy of Sciences, provides clues both to long-term non-progression and to AIDS vaccine development.

Long-term non-progressors are people who have been infected for more than eight to ten years without signs of clinical progression. "A critical issue in AIDS disease development is why infected people become sick at different rates," said Max Essex, DVM, PhD, chairman of the Harvard AIDS Institute and an author of the paper. "The possibility that patients with different rates of disease progression have different mutation profiles in their HIV has not been analyzed, except perhaps in relation to ZDV therapy," stated Tun-Hou Lee, DSc, senior author of the paper.

The Harvard researchers focused on the surface protein, or envelope, of HIV because it is the first target of the host immune system, and is involved in the binding of the virus to the host target cell. This protein, gp120, contains five variable regions (V1-V5) and five constant regions (C1-C5). The investigators found that long-term non-progressors had more changes in one of the constant regions, C3, and relatively fewer changes in the variable regions. This finding provides the first demonstration that differential selection pressure related to the emergence of HIV variants is associated with long-term non-progression. It also suggests that constant regions, such as C3, rather than variable regions, may be the particular target for immune response in long-term non-progressors.

Until now most vaccine candidates-whole-killed virus, unmodified gp120-tended to elicit immune responses targeting selected variable regions, such as V3. An implication of the current results is that vaccines designed to elicit strong selection pressure on the C3 region are likely to provide better protection than those vaccines targeting the variable regions.

The Harvard AIDS Institute is a university-wide organization dedicated to conducting and catalyzing research to end the worldwide AIDS epidemic. This study was done in conjunction with Fenway Community Health Center and the Boston Department of Health and Hospitals.

Reference: Wang W-K, Essex M, McLane MF, Mayer KH, Hsieh C-C, Brumblay HG, Seage G, and Lee T-H. Pattern of gp120 sequence divergence linked to a lack of clinical progression in human immunodeficiency virus type 1 infection. Proc Nat Acad Sci 1996;93:6693-97.

March 1, 1996 - Harvard AIDS Institute researchers have discovered that a subtype of HIV in Thailand spreads much more easily among heterosexuals than the U.S. subtype. "The Thai subtype was recently detected in the U.S.," said Max Essex, chairman of the Harvard AIDS Institute. "If it takes hold here, we could face a much more significant epidemic among heterosexuals."

As reported in today's Science, the Harvard researchers evaluated viruses from Thailand, where HIV subtype E is prevalent, and from the United States, where subtype B predominates. The scientists found that the Thai subtype grew much more efficiently in Langerhans' cells-cells that line the reproductive tract-than did the U.S. subtype. This result links viral growth in these cells to the efficient spread of HIV during heterosexual intercourse.

Essex, senior author of the Science paper, believes that efficient growth of HIV in Langerhans' cells may account for the explosive heterosexual spread not only of subtype E in Thailand, but also of other subtypes linked with significant heterosexual epidemics in Asia and Africa. Subtype B-the only subtype now prevalent in the United States-does not exhibit this same efficiency.

Essex adds that this finding has significant implications for AIDS vaccine development. "The fact that subtypes have different affinities for attaching to different kinds of cells is critical to vaccine development, because vaccines seek to block those kinds of attachments," Essex said. "To date, most vaccine prototypes have only targeted subtype B. Yet to be fully effective worldwide, AIDS vaccines must protect against all subtypes and against all modes of transmission."

The Harvard AIDS Institute is a university-wide organization that conducts and catalyzes research to end the worldwide AIDS epidemic. The Institute conducted the study in collaboration with investigators at Mahidol University and Chiang Mai University in Thailand, as well as other institutions in Boston.

Background Information
Scientists have detected nine subtypes of HIV-1, the AIDS virus now causing a worldwide epidemic. (The second AIDS virus, HIV-2, is found primarily in West Africa.) The HIV-1 subtypes have been designated A, B, C, D, E, F, G, H, and O. Subtype B is prevalent in the United States and Western Europe. Subtypes A, C, and D predominate in Africa; subtype C predominates in India. Thailand has both subtypes E and B.

Harvard's biological finding helps explain two epidemiological conundrums that have eluded scientists for years. First, a subtype B epidemic that started among injection drug users in Thailand subsequently plateaued at a relatively low level, with less than 100,000 people infected, while Thailand's subtype E epidemic has exploded among heterosexuals, with up to a million people infected. (This difference between the epidemics occurred even though B was present in Thailand several years before E.)

Second, heterosexual intercourse has to date accounted for 10 percent or less of HIV transmission in the United States and Western Europe, and yet more than 90 percent of HIV transmission in Asia and Africa.

The Harvard researchers point out that while differences in the rate of HIV heterosexual transmission may also be due to such factors as sexual behavior and the presence of other sexually transmitted diseases, none of the factors studied has yet adequately accounted for the widespread heterosexual epidemics in Asia and Africa.

Reference: Soto-Ramirez L, Renjifo B, McLane MF, Marlink R, O'Hara R, Sutthent R, Wasi C, Vithayasai P, Vithayasai V, Apichartpiyakul C, Auewarakul P, Cruz VP, Chui D-S, Osathanondh R, Mayer K, Lee T-H, and Essex M. HIV-1 Langerhans' cell tropism associated with heterosexual transmission of HIV. Science 1996;271:1291-93.

June 16, 1995 - Harvard AIDS Institute researchers have found that infection with the second AIDS virus (human immunodeficiency virus type 2, or HIV-2) sharply reduces the chances of becoming infected with HIV-1, the virus causing the worldwide AIDS epidemic. This finding, reported in today's Science, demonstrates for the first time in humans that protection against HIV-1 infection is possible, and may have important implications for AIDS vaccine development.

In a study of 756 women licensed as commercial sex workers in Dakar, Senegal, from 1985 to 1994, the researchers found that infection with HIV-2 reduced the women's chances of acquiring HIV-1 infection by approximately 70 percent. This reduction occurred despite a higher incidence of gonorrhea, which suggests that the HIV-2-infected women had not lessened their exposure to HIV-1 through behavioral change.

The study-a joint collaboration between the Harvard AIDS Institute and the University Cheikh Anta Diop in Dakar-has yielded a number of other important findings since 1985, including the initial identification of HIV-2, which has been confined primarily to West Africa. The research team also has shown that the rates of disease development and transmission are dramatically slower in people with HIV-2 than in people with HIV-1-observations that led to the idea that the weaker and less easily transmissible virus might protect against HIV-1 infection.

"Clearly, HIV-2 is triggering a resistance response that in some way protects against HIV-1 infection," said Phyllis Kanki, associate professor of pathobiology at Harvard and lead investigator of the study. "The next step will be to study the women in greater detail to learn precisely how this immunity is manifested."

"A vaccine that mimics the immunologic response to HIV-2 infection may offer a high degree of protection against HIV-1," said Max Essex, chairman of the Harvard AIDS Institute and an author of the Science paper. "This work shows that it may be possible to induce immunity to protect against very different strains of HIV if the formulation and dosing of test vaccines are optimal."

Ideally, the researchers say, a vaccine could stimulate an immune response similar to that triggered by HIV-2, but not expose patients to the risk of HIV-2 infection. This might be accomplished by engineering forms of the HIV antigens that mimic the natural infection with HIV-2. Related yet distinct viruses have been successfully used to vaccinate other diseases in humans and animals. The cowpox virus, for example, was used to generate the first vaccine and ultimately to eradicate smallpox.

"Since HIV-2 can lead to AIDS and death, we're not suggesting using it as a live vaccine," said Kanki. "But we can take advantage of the interference that occurs in nature. These findings suggest a new avenue for research into fine-tuning that natural protection and delivering it in the form of a safe vaccine."

The Harvard AIDS Institute is a university-wide organization that conducts and catalyzes research to stop the worldwide AIDS epidemic. Its collaborative study with the University Cheikh Anta Diop is the longest prospective study on HIV in Africa and one of the longest studies of HIV-infected people in the world.

Reference: Travers K, Mboup S, Marlink R, Guèye-Ndiaye A, Siby T, Thior I, Traoré I, Dieng-Sarr A., Sankalé JL, Mullins C, NDoye I, Hsieh C, Essex M, and Kanki P. Natural protection against HIV-1 infection provided by HIV-2. Science 1995;268:1612-15.

After studying infection with both viruses in the same group of people for eight years, the researchers believe that differences in the biologic composition of the two viruses account for the dramatically longer survival time with HIV-2, rather than differences related to the people infected with either virus.

"Perhaps the most significant result reported in the recent AIDS conference in Yokohama is the observation that a fraction of those infected with HIV-1-less than 5 percent-are "long-term survivors"-that is, they live for at least 10 years without developing symptoms of infection," said Max Essex, chairman of the Harvard AIDS Institute and an author of the Science paper. "This study suggests that, among those infected with HIV-2, long-term survival may be the rule rather than the exception."

Evidence of HIV-2, which is highly prevalent in many West African countries, was first found among Senegalese women in 1985 and is known to have been present in West Africa at least since the 1960s. The authors of the study point out that although case reports, hospital-based surveys, and cross-sectional studies have described the clinical characteristics of people infected with HIV-2, this is the first study to fully define the clinical history of HIV-2 infection and disease. It is also the first study to define for Africa the likelihood over time of developing full-blown AIDS after initial infection with either virus.

"Our study demonstrates definitively for the first time that the two viruses have very different likelihoods of causing AIDS," said Richard Marlink, executive director of the Harvard AIDS Institute and lead author on the study. "If we can determine, biologically, why HIV-2 causes less disease than HIV-1, then we may be able to develop therapies to help reduce the virulence of HIV-1. Moreover, with more than 10 million Africans now infected with HIV-1 or HIV-2, it is critical to document their likelihood of developing AIDS, both to predict the number of future AIDS cases for the region and to provide patients with information about their individual prognoses."

The study has more participants and a longer observation time than any other cohort study that has examined HIV-1 and HIV-2 infection in Africa, Marlink added. Study participants were 574 female commercial sex workers in Dakar, Senegal. The study, which has been ongoing since 1985, is a joint collaboration between the Harvard AIDS Institute, the University of Dakar, and the Universities of Tours and Limoges in France.

Reference: Marlink R, Kanki P, Thior I, Travers K, Eisen G, Siby T, Traore I, Hsieh C-C, Dia M, Gueye E-H, Hellinger J, Gueye-Ndiaye A, Sankale J-L, Ndoye I, Mboup S, and Essex M. Reduced rate of disease development after HIV-2 infection as compared to HIV-1. Science 1994;265:1587-90.