Abstract
The global AIDS pandemic continues to expand and in some regions of the world, such as southern Africa, the prevalence of HIV-1 infection exceeds 20%. The devastating spread of the virus in young women in these countries appears disproportional to overall risk of infection. Regions with high prevalence of HIV-1 are often also highly endemic for other pathogenic viruses including HSV, CMV and HTLV. We propose that acquisition by HIV-1 of the envelope glycoproteins of other viruses, in a process we call “natural pseudotyping,” expands the cellular tropism of HIV-1, enabling it to infect female genital epithelial cells directly and thereby dramatically increasing risk of infection during sexual intercourse. In this proof-of-concept study, we demonstrate that when HIV-1 co-infects T cells along with the gammaretrovirus xenotropic murine leukemia virus-related virus (XMRV), progeny HIV-1 particles are produced capable of infecting primary vaginal, ectocervical and endocervical epithelial cells. These cell types are normally resistant to HIV-1 infection. Infection of primary genital cells was neutralized by antisera against the XMRV glycoprotein, confirming that infection was mediated by the XMRV glycoprotein acquired through pseudotyping of HIV. Inhibition by AZT showed that active replication of HIV-1 occurred in these cells and ruled out non-specific endocytic uptake of the virus. These results demonstrate that natural pseudotyping can expand the tropism of HIV-1 to include genital epithelial cells and have potential implications for sexual transmission of the virus.
Highlights
The HIV-1 by Gag ELISA (HIV)/AIDS pandemic is primarily sustained by heterosexual transmission of HIV-1 and more than half of all new infections occur in young women
We demonstrated that lipid rafts play a role in the biology of this virus [26]. This observation further suggested xenotropic murine leukemia virus-related virus (XMRV) as a good model virus for studying natural pseudotyping of HIV-1 given that HIV-1 assembly and release occurs at lipid rafts [27,28,29,30,31,32,33,34], We explored whether XMRV and HIV-1 co-infection in T cells results in pseudotyped HIV-1 capable of infecting epithelial cell lines and primary cells from female lower genital tract epithelium
We sought to determine if natural pseudotyping of HIV-1 occurs when it co-infected the same cells along with the gammaretrovirus XMRV
Summary
The HIV/AIDS pandemic is primarily sustained by heterosexual transmission of HIV-1 and more than half of all new infections occur in young women. In the case of HIV-1, the attachment protein gp120 binds and sequentially to CD4 and chemokine receptors, primarily CXCR4 and CCR5 and this limits the tropism of HIV-1 to CD4+ T cells, macrophages, and dendritic cells [9,10,11,12,13,14,15,16,17] Retroviruses such as HIV-1 are capable of incorporating envelope glycoproteins of other viruses. Co-infection of HIV-1 permissive cells (CD4+ T cells, macrophages, and dendritic cells) by HIV1 and other viruses may allow HIV-1 to acquire the envelope glycoprotein (and cellular tropism) of the co-infecting virus We refer to this phenomenon as ‘‘natural pseudotyping’’ to distinguish it from pseudotyping through molecular genetic techniques as described above. We propose that this process may represent a mechanism that profoundly increases the likelihood of sexual transmission of HIV-1
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