Pathophysiology of HIV/AIDS

The HIV virus is commonly transmitted via unprotected sexual activity, blood transfusions, hypodermic needles, and from mother to child. Upon acquisition of the virus, the virus replicates inside and kills T helper cells, which are required for almost all adaptive immune responses. There is an initial period of influenza-like illness, and then a latent, asymptomatic phase. When the CD4 lymphocyte count falls below 200 cells/ml of blood, the HIV host has progressed to AIDS, a condition characterized by deficiency in cell-mediated immunity and the resulting increased susceptibility to opportunistic infections and certain forms of cancer.

Immunology

After the virus enters the body there is a period of rapid viral replication, leading to an abundance of virus in the peripheral blood. During primary infection, the level of HIV may reach several million virus particles per milliliter of blood.^[1]

This response is accompanied by a marked drop in the numbers of circulating CD4⁺ T cells. This acute viremia is associated in virtually all people with the activation of CD8⁺ T cells, which kill HIV-infected cells, and subsequently with antibody production, or seroconversion. The CD8⁺ T cell response is thought to be important in controlling virus levels, which peak and then decline, as the CD4⁺ T cell counts rebound. A good CD8⁺ T cell response has been linked to slower disease progression and a better prognosis, though it does not eliminate the virus.^[2]

During the acute phase, HIV-induced cell lysis and killing of infected cells by cytotoxic T cells accounts for CD4⁺ T cell depletion, although apoptosis may also be a factor. During the chronic phase, the consequences of generalized immune activation coupled with the gradual loss of the ability of the immune system to generate new T cells appear to account for the slow decline in CD4⁺ T cell numbers.

However, the symptoms of immune deficiency characteristic of AIDS do not appear for years after a person is infected, the bulk of CD4⁺ T cell loss occurs during the first weeks of infection, especially in the intestinal mucosa, which harbors the majority of the lymphocytes found in the body.^[3] The reason for the preferential loss of mucosal CD4⁺ T cells is that a majority of mucosal CD4⁺ T cells express the CCR5 coreceptor, whereas a small fraction of CD4⁺ T cells in the bloodstream do so.^[4]

HIV seeks out and destroys CCR5 expressing CD4⁺ cells during acute infection. A vigorous immune response eventually controls the infection and initiates the clinically latent phase. However, CD4⁺ T cells in mucosal tissues remain depleted throughout the infection, although enough remain to initially ward off life-threatening infections.

Continuous HIV replication results in a state of generalized immune activation persisting throughout the chronic phase.^[5] Immune activation, which is reflected by the increased activation state of immune cells and release of proinflammatory cytokines, results from the activity of several HIV gene products and the immune response to ongoing HIV replication. Another cause is the breakdown of the immune surveillance system of the mucosal barrier caused by the depletion of mucosal CD4⁺ T cells during the acute phase of disease.^[6]

This results in the systemic exposure of the immune system to microbial components of the gut’s normal flora, which in a healthy person is kept in check by the mucosal immune system. The activation and proliferation of T cells that results from immune activation provides fresh targets for HIV infection. However, direct killing by HIV alone cannot account for the observed depletion of CD4⁺ T cells since only 0.01–0.10% of CD4⁺ T cells in the blood are infected.

A major cause of CD4⁺ T cell loss appears to result from their heightened susceptibility to apoptosis when the immune system remains activated. Although new T cells are continuously produced by the thymus to replace the ones lost, the regenerative capacity of the thymus is slowly destroyed by direct infection of its thymocytes by HIV. Eventually, the minimal number of CD4⁺ T cells necessary to maintain a sufficient immune response is lost, leading to AIDS.

Cells affected

The virus, entering through which ever route, acts primarily on the following cells:^[7]

• Lymphoreticular system:
  • CD₄+ T-Helper cells
  • Macrophages
  • Monocytes
  • B-lymphocytes
• Certain endothelial cells
• Central nervous system:
  • Microglia of the nervous system
  • Astrocytes
  • Oligodendrocytes
  • Neurones – indirectly by the action of cytokines and the gp-120

The effect

The virus has cytopathic effects but how it does it is still not quite clear. It can remain inactive in these cells for long periods, though. This effect is hypothesized to be due to the CD₄-gp120 interaction.^[7]

• The most prominent effect of HIV is its T-helper cell suppression and lysis. The cell is simply killed off or deranged to the point of being function-leapses leading to the familiar AIDS complications, like infections and neoplasms (vide supra).
• Infection of the cells of the CNS cause acute aseptic meningitis, subacute encephalitis, vacuolar myelopathy and peripheral neuropathy. Later it leads to even AIDS dementia complex.
• The CD₄-gp120 interaction (see above) is also permissive to other viruses like Cytomegalovirus, Hepatitis virus, Herpes simplex virus, etc. These viruses lead to further cell damage i. e. cytopathy.

Molecular basis

For details, see:

• Structure and genome of HIV
• HIV replication cycle
• HIV tropism

References

1. Piatak, M., Jr, Saag, M. S., Yang, L. C., Clark, S. J., Kappes, J. C., Luk, K. C., Hahn, B. H., Shaw, G. M. and Lifson, J.D. (1993). "High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR". Science 259 (5102): 1749–1754. Bibcode:1993Sci...259.1749P. doi:10.1126/science.8096089. PMID 8096089.
2. Pantaleo G, Demarest JF, Schacker T, Vaccarezza M, Cohen OJ, Daucher M, Graziosi C, Schnittman SS, Quinn TC, Shaw GM, Perrin L, Tambussi G, Lazzarin A, Sekaly RP, Soudeyns H, Corey L, Fauci AS. (1997). "The qualitative nature of the primary immune response to HIV infection is a prognosticator of disease progression independent of the initial level of plasma viremia". Proc Natl Acad Sci U S A. 94 (1): 254–258. Bibcode:1997PNAS...94..254P. doi:10.1073/pnas.94.1.254. PMC 19306. PMID 8990195.
3. Mehandru S, Poles MA, Tenner-Racz K, Horowitz A, Hurley A, Hogan C, Boden D, Racz P, Markowitz M (September 2004). "Primary HIV-1 infection is associated with preferential depletion of CD4⁺ T lymphocytes from effector sites in the gastrointestinal tract". J. Exp. Med. 200 (6): 761–70. doi:10.1084/jem.20041196. PMC 2211967. PMID 15365095.
4. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, Nguyen PL, Khoruts A, Larson M, Haase AT, Douek DC (September 2004). "CD4⁺ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract". J. Exp. Med. 200 (6): 749–59. doi:10.1084/jem.20040874. PMC 2211962. PMID 15365096.
5. Appay V, Sauce D (January 2008). "Immune activation and inflammation in HIV-1 infection: causes and consequences". J. Pathol. 214 (2): 231–41. doi:10.1002/path.2276. PMID 18161758.
6. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, Blazar BR, Rodriguez B, Teixeira-Johnson L, Landay A, Martin JN, Hecht FM, Picker LJ, Lederman MM, Deeks SG, Douek DC (December 2006). "Microbial translocation is a cause of systemic immune activation in chronic HIV infection". Nat. Med. 12 (12): 1365–71. doi:10.1038/nm1511. PMID 17115046.
7. Textbook of Pathology by Harsh Mohan, ISBN 81-8061-368-2