Virus: Host Interactions in HIV Pathogenesis: Directions for Therapy

HIV was discovered about 25 years ago and has been well characterized for its biologic, genetic and antigenic properties. Because it attaches to CD4 and chemokine co-receptors (e.g. CCR5, CXCR4) treatments to reduce virus infection through decoys to CCR5 as well as gene therapy have been attempted. The role of chemokines in HIV infection merit further consideration. Anti-retroviral drugs have given great benefit to infected individuals progressing to disease but viral resistance and toxicities pose problems. Other challenges include the emergence of recombinant viruses, some involving different regions of the viral genome and various HIV-1 clades and groups. In addition, the replicative ability of different virus subtypes and groups of HIV-1 and HIV-2 can determine viral transmission and pathogenesis. The host genetic background and its influence on immune competence are important features in HIV pathogenesis. Newly discovered intracellular proteins (e.g. APOBEC-3G, TRIM 5) vary in expression, and offer novel targets for inducing HIV resistance.

The innate and adaptive immune systems can greatly affect the clinical course and include both humoral and cellular components. Anti- HIV substances such as virus-binding lectins and complement can eliminate the virus in a non-specific manner; neutralizing antibodies inactivate HIV with specificity. Innate cells such as NK,  T and dendritic cells (e.g. plasmacytoid dendritic cells) can provide an early and effective control of HIV infection and spread. Non-cytotoxic (eg. cytokine mediated) CD8+ T cells can suppress HIV pathogenesis. Anti-HIV specific CD4+ and CD8+ T lymphocytes also decrease virus replication and spread, but their possible role in a pathogenic course must be appreciated.

Importantly, insights into viral and host parameters that influence HIV pathogenesis can be gained from individuals during acute/early infection as well as those who remain healthy without therapy for more than 10 years (e.g. elite controllers). In addition, studies of HIV-exposed but not infected people should provide new avenues towards long-lasting control of HIV infection.