CHEMOKINE RECEPTORS AND HUMAN IMMUNODEFICIENCY VIRUS INFECTION

Paul D. Bieniasz and Bryan R. Cullen

Department of Genetics and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710

Received 12/15/97 Accepted 12/19/97

3. HIV AND SIV TROPISM

Additional evidence for the existence of primate lentivirus coreceptors derived from the observation that HIV/SIVs have a range of overlapping but readily distinguishable tropisms. For example, while many immortalized human T-cell lines can be infected by laboratory adapted HIV-1, HIV-2 and SIV strains, other CD4 positive cell lines are sometimes selectively permissive only for specific virus types (4). Heterogeneity in tropism is also evident within a given virus type. In the case of HIV-1, virtually all strains replicate efficiently in CD4+ peripheral blood lymphocytes (PBL). However many freshly isolated or primary strains are also able to propagate efficiently in primary macrophages but not in immortalized T-cell lines and are thus termed M-tropic. Conversely, other strains, particularly those which have been adapted to growth in immortalized T-cell lines (T-tropic) generally do not efficiently infect primary macrophages (6-9). A proportion of isolates (termed dual-tropic) are able to replicate well in both T-cell lines and primary macrophages in addition to PBL (10-12). Dual-tropic and T-tropic strains induce cell fusion in primary and immortalized T-cells and are also referred to as syncytium inducing (SI).

In almost all cases, the determinants of HIV/SIV tropism can be mapped to the viral envelope gene (13-19), thus indicating that tropism is restricted at the level of virus entry. A significant finding was that a major determinant of HIV-1 T- verses M-tropism is the third hypervariable (V3) region of the surface glycoprotein, gp120 (13-15). While other regions of the viral envelope (notably V1) have also been also shown in to influence HIV-1 tropism (17-19) it remains true that the tropism of a particular strain is very often determined by the V3 region of the viral envelope.

An important prediction arising from these data was that T-tropic and M-tropic HIV-1 strains, as well as HIV-2 and SIV, would make use of distinct coreceptors for virus entry. As we will discuss, this prediction proved at least partially accurate, and it appears that the role of the envelope in determining viral tropism is manifested at the level of coreceptor selection. In addition, there is variation in the 'promiscuity' of viral envelopes in that some are restricted to the use of a single coreceptor, whereas others are able to interact with several. It is becoming clear that (with a few exceptions) the spectrum of tropisms associated with primate lentiviruses can be largely explained by coreceptor utilization and distribution