A 38-year-old man has been HIV-positive since the age of 26 but has refused antiretroviral prophylaxis. His CD4 cell count, however, is still within normal limits, and the virus is undetectable in the blood. Genetic investigations clarify this apparent puzzle, demonstrating that this subject is homozygous for a mutation affecting a chemokine receptor necessary for HIV entry into the cell. Which of the following receptors is most likely involved?
HIV infection does not always progress to ove AIDS. In a few founate individuals (called non-progressors), the infection remains asymptomatic, with a stable CD4 cell count and low or undetectable viremia. It is not entirely clear whether these patients will eventually develop AIDS. Some are resistant to HIV infection because they carry two defective copies of the gene encoding the CCR5 coreceptor. There are 15 known coreceptors, of which CCR5 and CXCR4 are the best characterized. CCR5 is a receptor for b-chemokines and serves as a coreceptor for HIV internalization. Approximately one percent of Caucasians in the U.S. is homozygous for such a protective CCR5 variant, and 20% are heterozygotes. HIV infection follows a slower course in heterozygotes. Homozygotes for this protective CCR5 variant are not present among Black and Asian populations. Recently, a variant haplotype of CXCR1 (a leukocyte receptor for fractalkine) has been linked to rapid progression of HIV infection in homozygous individuals. Thus, investigations on HIV coreceptors are beginning to explain the variability in progression and severity of HIV infection among individuals. CD4 (2nd Choice) is an impoant receptor of helper T lymphocytes, macrophages, and Langerhans cells. It acts as the primary receptor for HIV binding. Binding to CD4, however, is not sufficient for the entry of HIV into the cells. The viral envelope gp120 protein (4th Choice) first binds CD4. This results in a conformational change in gp120 that allows this protein to bind coreceptors. Such coreceptors are present on lymphocytes and macrophages and normally serve as binding sites for chemokines. Once gp120 binds to CD4 and a coreceptor, a second viral protein, gp41, facilitates fusion of the viral envelope with the plasma membrane, allowing "injection" of the viral core into the cell. Neither CD8 (5th Choice) nor the receptor for TNF-a plays a role in HIV binding to cells.
CCR5
CD4
CD8
Gp120