Infection with HIV

Many of the clinical features of HIV infection can be ascribed to the profound immune deficit that develops in infected individuals. HIV is immunosuppressive because it infects cells of the immune system and ultimately destroys them. An understanding of this process is helpful in interpreting tests used in monitoring the disease and may explain the failure of immunotherapy and the difficulties in developing vaccines for

HIV.

The most obvious target of the virus is a subset of thymus-derived (T) lymphocytes carrying the surface molecule CD4, which has been shown to bind the envelope glycoprotein of HIV (gp120). CD4 is also present on a large proportion of monocytes and macrophages, Langerhans' cells of the skin and dendritic cells of all tissues. More recently it has also become clear that virus entry also requires co-receptors, most of which are members of the seven transmembrane-spanning G proteincoupled receptor family. In the immune system these principally function as receptors for chemokines that orchestrate the migration, differentiation and function of leucocytes during immune responses. Two receptors, CCR5 and CXCR4, are particularly important. CCR5 (R5) is widely expressed on lymphocytes, macrophages, dendritic cells and cells of the rectal, vaginal and cervical mucosae. Virus strains able to infect primary macrophages (macrophage (M) or R5 tropic viruses) use CCR5 as a co-receptor. Only R5 strains are detected early after infection, while both R5 viruses and strains that infect T cells and use CXCR4 (T or X4 tropic viruses) are found late in infection. These data suggest that R5 strains are important for transmission of HIV while X4 variants arise during the course of infection and may be responsible for T-cell loss and disease progression. Even stronger evidence that CCR5-using M tropic viruses transmit infection, comes from the observation that individuals homozygous for a 32 base pair deletion of CCR5 show greatly increased resistance to HIV infection. Several other chemokine receptors have been shown capable of acting as co-receptors in vitro and polymorphisms in CCR2 as well as CCR5 and SDF1 (the ligand for CXCR4), are associated with different rates of progression to AIDS.

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