Tissue Damage. Cofactors. Conclusion

Tissue Damage. While pathogenic effects of HIV infection of CD4⁺ T cells are well documented, little is known about its effect on other cells, especially those that are not part of the immune system. Based on studies involving staining of pathological specimens, it appears that HIV may directly infect glial cells in the brain and some epithelial and enterochromaffin cells in the intestinal mucosa.

Although highly productive HIV infection in such cells has not been demonstrated, it is possible that HIV could alter the function of the infected cells and contribute to the myelin depletion and the malabsorption that occur in many infected individuals.

HIV could also lead to tissue damage even without directly infecting the cells involved. Antibodies complexed to their cognate antigens (immune complexes) can also cause tissue damage. Immune complexes circulating in the blood can attach to cells (e.g., platelets) and lead to the destruction of those cells. The immune complexes can also be deposited in various tissues, including the kidneys and joints, leading to inflammation and tissue injury.

Because gpl20 has several regions of homology with other cellular proteins, (e.g., IL-2), cross-reacting anti- HIV antibodies, as well as anti-idiotypic antibodies (antibodies to the antibodies) could conceivably lead to autoimmune disease. Finally, the lack of proper CD4⁺ T cell help in regulating antibody production could lead to an overproduction of harmful antibodies.

Cofactors. Other factors, especially infections by other viruses, can exacerbate HIV-related disease. Because many viruses are transiently immunosuppressive, they can further weaken the ability of the immune system to control HIV. Reciprocally, the immunosuppressive effects of HIV allow other infections to be more aggressive. Infections also activate T cells, which increases HIV gene expression and virus production.

Enhancement of HIV production could also occur if an HIV-infected cell is superinfected with another virus. Several viruses, including cytomegalovirus and hepatitis В virus, produce trans-acting proteins that affect the regulatory sequences in the HIV LTR. Under experimental conditions these trans-activators lead to an increase in the expression of the genes under the control of the HIV LTR. Since coinfection of brains cells with HIV and cytomegalovirus has been reported, it is possible that the latter increases HIV expression in these cells.

Finally, the various opportunistic infections and cancers that characterize AIDS can weaken HIV- infected individuals without directly affecting HIV replication. The pathological effects of these opportunistic infections and cancers can be generalized (e.g., weakness, loss of appetite, and weight loss), or they can be localized to specific tissues, leading to organ failure in severe cases. Ultimately, the spread of these infections or cancers, rather than the spread of HIV itself, kills the infected individual.

Conclusion. Research in the 1980s has delineated the structure and genetic organization of HIV and shed light on the interaction of the virus with the infected cell. This work provides a basis for rational approaches to the development of drugs and vaccines to control the spread of AIDS.

Current information about HIV also reveals several features of the infection that make it difficult to suppress HIV replication and block HIV infection. Controlling HIV production has been hindered by the very nature of the retrovirus life cycle, which involves integration in the host genome and activation by cellular factors. Retroviral genes can be indefinitely maintained in a latent state in cells, allowing escape from immune clearance. Therefore, we might need to develop novel therapies (e.g., blocking integration).

Development of an HIV vaccine has been hindered by the heterogeneity of the virus, especially the envelope glycoprotein. Unlike other viruses with relatively invariant envelope proteins and few viral strains, many HIV variants can be found among and within infected individuals. Antibodies to the envelope glycoprotein of one HIV strain generally do not neutralize other HIV strains. A more detailed understanding of common structural features of the envelope glycoproteins is required if we are to develop drugs or antibodies that neutralize all HIV strains.

Knowledge about HIV and AIDS is increasing at an astonishing rate. With this wealth of information comes hope for effective treatment and prevention strategies in the 1990s.

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