AIDSWEEKLY Plus; Monday, July 18, 2005
Staff Medical Writers

Study 1: HIV-1 envelope V2 region influence HIV entry and spread in macrophages.

"Human immunodeficiency virus type 1 (HIV-1) isolates vary in their ability to infect macrophages. Previous experiments have mapped viral determinants of macrophage infectivity to the V3 hypervariable region of the HIV-1 envelope glycoprotein," scientists in the United States report.

"In our earlier studies, V1 and V2 sequences of HIV-1 were also shown to alter the ability of virus to spread in macrophage cultures, whereas no effect was seen in lymphocyte cultures.

"In the present study," said investigators, "determinants that allowed certain HIV-1 clones to infect and spread in macrophages were primarily mapped to the V2 region and were found to act by influencing early events of viral infection."

"By an assay of viral entry into macrophages, it was shown that viruses with the V2 region from the Ba-L strain of HIV-1 had >10-fold-higher entry efficiency than viruses with the V2 region derived from the NL4-3 strain.

"V1 region differences between these groups caused a twofold difference in entry. The known low expression of CD4 on macrophages appeared to be important in this process," wrote B.L. Walter and colleagues at the U.S. NIAID in Hamilton.

"In entry assays conducted with HeLa cell lines expressing various levels of CD4 and CCR5," continued Walter, "low levels of CD4 influenced the efficiency of entry and fusion which were dependent on viral V1 and V2 envelope sequences. In contrast, no effect of V1 or V2 was seen in HeLa cells expressing high levels of CD4."

The authors concluded, "Thus, the limited expression of CD4 on macrophages or other cell types could serve as a selective factor for V1 and V2 envelope sequences, and this selection could in turn influence many aspects of AIDS pathogenesis in vivo."

Walter and colleagues published their study in the Journal of Virology (Role of low CD4 levels in the influence of human immunodeficiency virus type 1 envelope V2 and V2 regions on entry and spread in macrophages. J Virol. 2005 Apr;79(8):4828-37.

For additional information, contact B. Chesebro, NIAID, Persistent Viral Diseases Laboratory, Rocky Mt Laboratories, 903 S 4th St., Hamilton, MT 59840, USA.

Study 2: Rodent cells support key functions of HIV-1 Nef.

According to a study from Germany, "After infection with human immunodeficiency virus (HIV), progression toward immunodeficiency is governed by a complex interplay of viral and host determinants.

"The viral accessory protein Nef is a key factor for the development of AIDS. Strains of HIV and simian immunodeficiency virus that lack functional Nef genes either do not induce AIDS or do so only after a significant delay."

"The validity of a transgenic-small-animal model for de novo infection by HIV will depend on its ability to recapitulate the actions of critical factors of viral pathogenicity, such as Nef.

"We assessed the ability of rat, mouse, and hamster cells to support key effector functions of Nef. In cell lines from rodents, the subcellular distribution of wild-type HIV type 1 strain SF2 Nef and mutants was comparable to that in human cells," wrote O.T. Keppler and coworkers at the University of Heidelberg.

"Nef downregulated human CD4 from the cell surface, was associated with p21-activated kinase activity, and enhanced the infectivity of HIV-1 virions.

"Importantly, these Nef-induced effects, as well as the downregulation of rat CD4 and major histocompatibility complex class I molecules, could also be demonstrated in primary T lymphocytes and macrophages from human CD4-transgenic rats," the authors reported.

"Thus, HIV-1 Nef exerts key functions in rodent cells. In line with our ongoing efforts to establish a transgenic-rat model of HIV disease, these results indicate that important aspects of viral pathogenesis could be addressed in a transgenic-rodent model permissive for de novo infection and that such a model would be valuable for evaluating the function of Nef in vivo," concluded investigators.

Keppler and colleagues published their study in the Journal of Virology (Rodent cells support key functions of the human immunodeficiency virus type 1 pathogenicity factor nef. J Virol. 2005 Feb;79(3):1655-65.

For more information, contact O.T. Keppler, University Heidelberg, Department Virology, Neuenheimer Feld 324, D-69120 Heidelberg, Germany.

Study 3: Separate HIV Nef domains are required to affect MHC-1 and CD4 cells.

"Human immunodeficiency virus type 1 (HIV-1) Nef is a critical protein that is necessary for HIV pathogenesis. Its roles include the disruption of major histocompatibility complex class I (MHC-I) and CD4 trafficking to promote immune evasion and viral spread.

"Mutational analyses have revealed that separate domains of Nef are required to affect these two molecules," investigators in the United States report.

"To further elucidate how Nef disrupts MHC-I trafficking in T cells," wrote M. Williams and colleagues at the University of Michigan, "we examined the role of protein domains that are required for this function (N-terminal alpha helix, polyproline, acidic, and oligomerization domains)."

The authors concluded, "We found that each of these regions was required for Nef to disrupt the transport of HLA-A2 to the cell surface and for Nef to coprecipitate with HLA-A2."

Williams and colleagues published their study in the Journal of Virology (Human immunodeficiency virus type 1 Nef domains required for disruption of major histocompatibility complex class I trafficking are also necessary for coprecipitation of Nef with HLA-A2. J Virol. 2005 Jan;79(1):632-6.

For additional information, contact K.L. Collins, University Michigan, Department Internal Medicine, 4301 MSRB111, Box 0638, 1150 W Med Center Dr., Ann Arbor, MI 48109, USA.

The information in this article comes under the major subject areas of Ann Arbor, MI, USA, HIV/AIDS, MHC-1, CD4 Cells, HIV-1 Nef Gene and Viral Pathogenesis.

This article was prepared by AIDS Weekly editors from staff and other reports.

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