Molecular details of the deadly handshake between HIV glycoproteins and their cell surface receptors have been elucidated. The HIV envelope contains two noncovalently associated glycoproteins, surface gp120 and the transmembrane protein gp41. The initial step in infection is the binding of the gp120 envelope glycoprotein to CD4 molecules, which leads to a conformational change that creates a new recognition site on gp120 for the coreceptors CCR5 or CXCR4. Binding to the coreceptors induces conformational changes in gp41 that exposes a hydrophobic region called the fusion peptide at the tip of gp41. This peptide inserts into the cell membrane of the target cells (e.g., T cells or macrophages), leading to fusion of the virus with the host cell. After fusion, the virus core containing the HIV genome enters the cytoplasm of the cell.
Once internalized, the RNA genome of the virus undergoes reverse transcription, leading to the synthesis of double-stranded complementary DNA (cDNA; proviral DNA) (see
Fig. 5.38 ). In quiescent T cells, HIV cDNA may remain in the cytoplasm in a linear episomal form. In dividing T cells, the cDNA circularizes, enters the nucleus, and is then integrated into the host genome. After integration, the pro-virus may be silent for months or years, a form of latent infection. Alternatively, proviral DNA may be transcribed, leading to the expression of viral proteins that are required for the formation of complete viral particles. HIV infects memory cells and activated T cells but is inefficient at productively infecting naïve (resting) T cells.
Completion of the viral life cycle in latently infected cells occurs only after cell activation, and in the case of most CD4+ T cells, virus activation results in death of the infected cells. Activation of T cells by antigens or cytokines upregulates several transcription factors, including NF-κB, which moves from the cytosol into the nucleus. In http://ebooksmedicine.net
Budding and release of mature virion
Fig. 5.38 The life cycle of HIV showing the steps from viral entry to production of infectious virions. (Adapted from Wain-Hobson S: HIV. One on one meets two. Nature 384:117, 1996.) the nucleus, NF-κB binds to regulatory sequences within several genes, including genes for cytokines and other immune mediators, promoting their transcription. The long-terminal-repeat sequences that flank the HIV genome also contain NF-κB–binding sites, so binding of the transcription factor activates viral gene expression. Imagine now a latently infected CD4+ cell that encounters an environmental antigen. Induction of NF-κB in such a cell (a physiologic response) activates the transcription of HIV proviral DNA (a pathologic outcome) and leads ultimately to the production of virions and to cell death. Furthermore, TNF and other cytokines produced by activated macrophages also stimulate NF-κB activity and thus lead to production of HIV RNA. Thus, it seems that HIV thrives when the host T cells and macrophages are physiologically activated, a situation that can be described as “subversion from within.” Such activation in vivo may result from antigenic stimulation by HIV itself or by other infecting microorganisms. HIV-positive individuals are at increased risk for recurrent infections, which leads to increased lymphocyte activation and production of proinflammatory cytokines. These, in turn, stimulate more HIV production, loss of additional CD4+ T cells, and more infections. Thus, it is easy to see how HIV infection sets up a vicious cycle that culminates in inexorable destruction of the immune system.
Mechanism of T-Cell Depletion in HIV Infection