Once isolated from the AIDS epidemic, the southern African nations of Botswana, Zimbabwe, Namibia, South Africa, and Swaziland were a redoubt of relatively low infection rates and prevalence. Now the disease has slammed into the region with a vengeance, infecting as many as one in four adults in some countries, and Max Essex, chair of the Harvard AIDS Institute, thinks he may know why.

HIV-1 comes in five major genetic subtypes, sometimes called clades, and HIV-1C is by far the most common subtype in southern Africa. One theory chalks up HIV-1C’s dominance in the region to a "founder effect"--that while HIV-1C got into the population in that part of the world and took off, if another subtype of HIV (such as HIV-1B, the prevailing subtype in the U.S. and Europe) had arrived first, and in a significant way, it might have kindled a very similar, fast-moving epidemic. Researchers who argue for the founder effect point out that while other HIV subtypes were, indeed, present in southern Africa before the HIV-1C-driven epidemic, they didn’t ignite such a severe epidemic because these infections occurred in populations compartmentalized by race and sexual preference.

Essex, who is also chair of the School’s Department of Immunology and Infectious Diseases, sees things differently: "The best evidence and all the epidemiologic studies suggest that HIV-1C is transmitted faster" than the four other subtypes. In Essex’s view it took HIV-1C to cause an AIDS epidemic the size and scope of the one sweeping through southern Africa, where infection rates are 25 to 50 times higher than in the U.S.

Marshaling clues from research done in his lab and elsewhere, Essex argues that HIV-1C has attributes that make it inherently more transmissible through heterosexual intercourse than other HIV subtypes. He also says that HIV-1C is inherently more pathogenic. Essex has sketched out his arguments in two pieces: "State of the HIV Pandemic," an editorial published in the November/December 1998 issue of the Journal of Human Virology, and "Human Immunodeficiency Viruses of the Developing World," a review article to be published this fall in volume 53 of Advances in Virus Research.

Like all HIV subtypes, HIV-1C infects cells in the mucosal linings of the cervix and the vagina by grabbing on to the CCR5 chemokine co-receptors on their surfaces. HIV latches on to a different co-receptor, labeled CXCR₄, when infecting lymphocytes circulating in the blood. Essex says one feature that distinguishes HIV-1C from other subtypes is that a much higher proportion of the clade appears to have an affinity for the CCR5 co-receptor. He believes that this predominance of "ccr5 tropism" in HIV-1C suggests that the subtype has an easier time getting into the cells in the mucosal linings of the cervix and the vagina and, therefore, is more easily transmitted from men to women through intercourse.

Essex’s second key point concerns HIV-1C replication rates and the resulting viral load. HIV-1C is a retrovirus, which means it reproduces itself by utilizing the reverse transcriptase enzyme to splice its genomic identity into the DNA of an unsuspecting host immune cell. The virus is replicated when this splice is "switched on" and transcribed into a fresh batch of HIV RNA. What Essex and his colleagues have shown is that when HIV-1C’s genomic identity is sneaked into the host cell’s DNA, the subtype has an added advantage: the genomic material of HIV-1C carries with it one, and often two, extra lengths of genetic code called " kb enhancer sites." These kb enhancer sites (about 10 nucleotides long) govern transcription; more kb enhancer sites mean more transcription--and that means, in Essex’s words, "more raw material, more virus particles." Moreover, this kb enhancer site—governed transcription gets revved up in the presence of tumor necrosis factor-a, a cytokine produced in large amounts by cells in reproductive tracts infected by sexually transmitted diseases, which perhaps helps explain the association between heterosexual HIV transmission and other sexually transmitted diseases. Even without tumor necrosis factor-a, another run-of-the-mill, housekeeping cell protein called rel-p65 will activate the kb enhancer sites.

Essex’s ideas about HIV-1C and its special attributes are important for a couple of reasons. First, they bolster the view that the course of the AIDS epidemic--who gets infected and at what rate--has been driven, to a large extent, by the characteristics of the HIV subtypes. Second, they underscore Essex’s long-held position that an effective vaccine must be based on the prevalent subtype of HIV. David Katzenstein, a Stanford AIDS researcher with extensive experience in Africa, says Essex’s and other people’s work on HIV-1C point to the conclusion that "you would want any southern African AIDS vaccine to be HIV-1C effective, if not specific." Jose Esparza, a vaccine development adviser to UNAIDS, says Essex has "an interesting theory, which needs to be confirmed with more research." He also notes that some of the rapid increase in HIV-1 might be an artifact of UNAIDS increasing its estimates of aids prevalence in southern Africa.

-- Peter Wehrwein