AIDSWEEKLY Plus, Monday, 9 June 1997
Daniel J. DeNoon, Senior Editor
Who, or what, are bob and bonzo?
The answer is expected to provide insight into an as-yet unanswered question about HIV infection: how do macrophage- tropic viral strains - which are responsible for the vast majority of sexual transmissions - infect T cells?
The answer may lie in monkey-cell receptors dubbed "bob" and "bonzo". These receptors (there are at least two, but no more than five) are expressed on rhesus monkey T cells and on some human T-cell lines and peripheral blood mononuclear cells (PBMCs). They apparently mediate T-cell infection by macrophage-tropic (M-tropic) viral strains independently of the CXCR4 coreceptor employed by T-cell-tropic (T-tropic) strains.
The findings are of great interest in understanding, and preventing, HIV infection. Despite the presence of both M- tropic and T-tropic HIV strains in typical viral inocula, it is the less virulent M-tropic strains that nearly always establish initial infection. T-tropic strains appear only later in the course of infection: so how do the M-tropic strains spread infection to T cells?
To answer this and other questions regarding sexual transmission of HIV, Preston A. Marx of the Aaron Diamond AIDS Research Center, Rockefeller University, New York, took advantage of the rhesus macaque model of infection using simian immunodeficiency virus (SIV) or chimeric simian/human immunodeficiency virus (SHIV).
Marx described his studies in a presentation to the 9th Annual Meeting of the National Cooperative Vaccine Development Groups for AIDS (NCVDG), held May 4-7, 1997, in Bethesda, Maryland.
Marx and colleagues used a flexible feeding tube to non- traumatically introduce cell-free virus into the vaginal vault, penile urethra, or rectum of the animals. They then carefully examined the mucosa of the infected animals to trace, at the cellular level, the earliest stages of SIV infection.
SIVmac with dual M- and T-tropism readily crossed the intact epithelium of the vagina, penile urethra, or rectum of inoculated animals.
Dual-tropic SHIV[89.6] and T-tropic SHIV[33] were able to infect across the vaginal mucosa, but M-tropic SHIV[162] was not.
"Thus it is not tropism per se but the robustness of the virus that is responsible for infection," Marx said.
Interestingly, only cell-free virus was infectious when administered via the vagina: cell-associated virus was more likely to cross the genital and rectal mucosa than cell- associated virus.
Cellular studies identified infected mucosal dendritic cells in the first week of infection. These cells, when cultured with resting T cells, support SIVmac replication in vitro.
Genetically diverse strains of SIV all used the monkey CCR5 receptor for cell entry. Unlike T-tropic HIV strains, which use the CXCR4 coreceptor, T-tropic SIV strains use the CCR5 receptor. But Marx and colleagues found that SIV - and HIV-2 - is able to replicate in cells lacking CCR5.
The researchers found that both rhesus and human CCR5 could act as a coreceptor for divergent SIV strains, including those from macaques(SIVmac), sooty mangabeys (SIVsm), and chimpanzees (SIVcpz). The DNA sequences of CCR5 from all of these species were closely homologous to human CCR5.
"All SIVs tested used all CCR5s but not CXCR4," Marx wrote in his presentation abstract. "However, they were dual tropic, apparently using an unknown T-cell coreceptor."
Analysis thus far has shown that there are at least two previously unidentified T-cell coreceptors: bob and bonzo.
"The SIV T-cell receptor is not CXCR4, but is expressed by some human T-cell lines and by PBMCs," Marx said.
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