Failure of human immunodeficiency virus entry and infection in CD4-positive human brain and skin cells

Abstract

CD4 molecules on human cells function as a major receptor for human immunodeficiency virus (HIV); however, certain CD4-negative cell types may also be susceptible to infection. Therefore, we attempted to quantitate the relationship between HIV infection and CD4 expression on human cell lines before and after introduction of the CD4 gene by using a retrovirus vector. Prior to introduction of the CD4 expression vector, low levels of HIV infection were detected by a sensitive focal immunoassay on all three cell types studied. With several HIV strains in clones of human cervical carcinoma (HeLa) cells expressing different levels of CD4, HIV titer increased with increasing CD4 expression. In contrast, in squamous cell carcinoma cells (SCL1) and astroglial cells (U87MG), even high levels of CD4 expression failed to augment HIV infection. The CD4 protein expressed in these two cell lines had the expected molecular weight and was capable of binding HIV virions. However, in contrast to CD4-positive HeLa cells, CD4-positive U87MG and SCL1 cells were unable to form syncytia when cultured with cells expressing HIV envelope protein. Thus, the inability of HIV to infect these cells appeared to be due to lack of fusion between HIV virion envelope proteins and CD4-positive cell membranes. This block is infectivity was overcome when cells were infected with HIV which was pseudotyped with the envelope protein of amphotropic murine leukemia virus. Thus, in addition to CD4, other cell surface molecules appear to be required for successful HIV entry into and infection of these two human cell lines.

Specific CD4 down-modulating compounds with potent anti-HIV activity

“…As three CD4 binding events are needed to efficiently activate HIV-1 Env trimers [58], multimeric CD4 binding is required for HIV infection, further implying that CD4 receptor density has a crucial role in effective HIV infection [59 -64]. Chesebro et al reported that the HIV titer in clones of human cervical carcinoma (HeLa) cells expressing different (low) levels of CD4 and infected with laboratory strains of HIV-1 increased with increasing CD4 expression [59]. Also primary HIV-1 isolates infected HeLa-CD4 cell clones that have distinct quantities of CD4 in direct proportion to cellular CD4 expression [60].…”

Change in tropism upon immune escape by human immunodeficiency virus

“…Both viruses infect T-cell lines, but Gun-1v also infects CD4 ϩ BT cells derived from the brain (35) and a glioma cell line transfected with CD4, U87-CD4 (32). Previous studies had shown that other diverse HIV-1 strains are not able to infect U87-CD4 cells (5,6).…”

Multiple extracellular domains of CCR-5 contribute to human immunodeficiency virus type 1 entry and fusion

“…Subsequent to the Env-CD4 interaction, a number of conformational changes in gp120 and probably in CD4 take place, leading to virus entry or syncytium formation (reviewed in references 58 and 83). These post-CD4 binding events are not completed in most nonhuman cell lines and in some human cell lines expressing human CD4, and membrane fusion fails to occur (5,20,23,53). It was suggested that these cells lack a component necessary for the fusion and entry processes to be completed (13,35,41).…”