Evidence that HIV-2 can infect CD4-negative cells

Human Immunodeficiency Virus Type 2, also known as HIV-2, is prevalent in West Africa and has spread recently to the western coastal region of India and to Europe. Compared to HIV-1 HIV-2’s mortality rate is thought to be a third lower and appears to be closer to the Simian Immunodeficiency Virus or SIV. As of 1999 it is known that all three types of immunodeficiency virus interact in some fashion with the CD4 cell surface and a co-receptor triggered by contact with the viral protein gp120. It is known that HIV-1 uses CCR5 and CXCR4 as its major co-receptors, but SIV and HIV-2 can use other co-receptors besides CCR5 and CXCR4 for infection in CD4+ cells.
Clapham, McKnight, and Weiss in 1992 showed that one strain of HIV-2 was able to successfully fuse cell to cell and have an efficient infection in CD4- human cells, while other strains were still dependent on CD4 or sCD4 (soluble CD4) for fusion. Reeves et al. in June of 1999 wanted to see if primary HIV-2 strains could infect CD4- cells that expressed either CCR5 or CXCR4 receptors.
They began by characterizing the co-receptors used by HIV-1, HIV-2, and SIV strains in CD4+ cells and found that compared to HIV-1, HIV-2 did use a variety of co-receptors for infection in almost all the viral strains but predominately CCR5 and CXCR4. They then tested for CD4-independent infection for the different HIV-2 strains using CD4- cells. The researchers concluded that certain strains could produce an effective infection in the cells using only CCR5 or CXCR4 receptors. To verify this, Reeves et al. used specific ligands of CCR5, CXCR4, and CD4 and confirmed that infection could occur independent of CD4 with CCR5 or CXCR4.
Overall, they found that there were 7 HIV-2 strains that used CCR5 and/or CXCR4 to infect CD4+ cells, but in CD4- cells 2 strains used only CXCR4, 2 strains used only CCR5, and 3 used neither CCR5 nor CXCR4 efficiently.
In comparing HIV-1, HIV-2, and SIV, they showed that HIV-2 and SIV are less reliant on CD4 for infection and that certain strains using CCR5 to infect CD4- cells levels were very similar to SIV strains in CD4 independent infection.
It is unknown why, but astrocytes although not expressing CD4, in vivo can be infected with HIV-1. Reeves et al. then determined whether astrocytes, CD4- cells, were susceptible to infection. Results showed that infection occurred via the CXCR4 receptor and that the concentration of the receptor might play a role in the efficiency of infection.
Thus the ability of HIV-2 to infect a cell independent of CD4 depends on the cell type and the concentration of co-receptors on the cell surface. The researchers note that there could be other receptors or factors that have yet to be identified. Co-receptors could have different conformational changes in different cells or could exist as oligomers, which would influence their activity and identification.
It is theorized that the original SIV and HIV strains used only one receptor and then evolved to the two co-receptor mechanism. This explains the difference between the different types of immunodeficiency viruses and variation of the strains within the sub-types. It is unknown why HIV needs 2 co-receptors to infect a cell, but it does seem selective pressures to gain immune resistance have evolved to make it harder for the body to inhibit viral infection. The fact that there are differences between types and strains make HIV mechanism difficult to understand and makes HIV treatment even more difficult to design.

Jessica Lahre


Reeves, J. et al. (1999). Primary Human Immunodeficiency Virus Type 2 (HIV-2)
Isolates Infect CD4-Negative Cells via CCR5 and CXCR4: Comparison with
HIV-1 and Simian Immunodeficiency Virus and Relevance to Cell Tropism In
Vivo. Journal of Virology. 73 (9): 7795-7804.