HIV AIDS pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] ; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [3]

Overview

Human Immunodeficiency virus causes AIDS by depleting CD4+ T helper lymphocytes. T lymphocytes are essential to the immune response and without them, the body cannot fight infections or kill cancerous cells. Thus the weakened immune system allows opportunistic infections and neoplastic processes. The mechanism of CD4+ T cell depletion differs in the acute and chronic phases, to sum it all AIDS has a complex pathophysiology.[1]

Pathophysiology

Thin-section transmission electron micrograph (TEM) depicting the ultrastructural details of two ”human immunodeficiency virus” (HIV) virions

Role of GALT in Pathogenesis

  • Port of entry for HIV infection is mostly through direct blood inoculation or exposure through genital mucosal surface. The gastrointestinal tract contains a large amount of lymphoid tissue, making it an ideal place for replication of Human Immunodeficiency Virus. GALT plays a role in HIV replication. [6]
  • GALT has been found to have the following characteristics:
    • Site of early viral seeding.
    • Establishment of the pro-viral reservoir.
  • The proviral GALT reservoir contributes to the following:
  1. Difficulty in controlling the infection.
  2. Difficulty in reducing the level of HIV provirus through sustained ART.[7] Various studies measuring the CD44 in GALT, have shown the relatively less reconstitution with ART, than that observed in peripheral blood.[8][9]
Image obtained from AIDSinfo.org [1]

Coinfections

Effect of Geographic Area on Opportunistic Infection

The opportunistic infection in AIDS patient reflect the pathogen that are common in that area.

  • In USA: Person with AIDS tends to present with commensal organism such as Pneumoncystis and Candida.
    • In a study done by National Center of HIV/AIDS,[10] PCP was the most common AIDS-defining opportunistic infection to occur first.
      • PCP was the first OI to occur for 36% of HIV-infected persons.
      • The most common incident AIDS-defining OI (274 cases per 1000 person-years).
      • The most common AIDS-defining OI to have occurred during the course of AIDS (53% of persons who died with AIDS had PCP diagnosed at some time during their course of AIDS).
  • In developing nations: AIDS patients tends to present with Tuberculosis, as it is more prevalent in those countries.

A. The Major Pulmonary Illnesses

  • Pneumocystis jiroveci is present in this lung impression smear, using Giemsa stain

    Pneumocystis jiroveci is present in this lung impression smear, using Giemsa stain

  • Scanning electron micrograph (SEM) of a number of Gram-positive Mycobacterium tuberculosis bacteria

    Scanning electron micrograph (SEM) of a number of Gram-positive Mycobacterium tuberculosis bacteria

Pneumocystis jiroveci Pneumonia

  • Pneumocystis jiroveci pneumonia (originally known as Pneumocystis carinii pneumonia, often abbreviated PCP) is relatively rare in normal, immunocompetent people but common among HIV-infected individuals. Before the advent of effective treatment and diagnosis in Western countries it was a common immediate cause of death.
  • In developing countries, it is still one of the first indications of AIDS in untested individuals, although it does not generally occur unless the CD4 count is less than 200 per µl.

Tuberculosis

  • Among infections associated with HIV, tuberculosis (TB) is unique in that it may be transmitted to immunocompetent persons via the respiratory route, is easily treatable once identified, may occur in early-stage HIV disease, and is preventable with drug therapy. However, multi-drug resistance is a potentially serious problem.
  • Even though its incidence has declined because of the use of directly observed therapy and other improved practices in Western countries, this is not the case in developing countries where HIV is most prevalent.
  • In early-stage HIV infection (CD4 count >300 cells per µl), TB typically presents as a pulmonary disease.
  • In advanced HIV infection, TB may present atypically and extrapulmonary TB is common infecting bone marrow, bone, urinary and gastrointestinal tracts, liver, regional lymph nodes, and the central nervous system (Decker and Lazarus, 2000).

B. The Major Gastro-intestinal Illnesses

Esophagitis

  • Esophagitis is an inflammation of the lining of the lower end of the esophagus (gullet or swallowing tube leading to the stomach). In HIV infected individuals, this could be due to fungus (candidiasis), virus (herpes simplex-1 or cytomegalovirus). In rare cases, it could be due to mycobacteria (Zaidi and Cervia, 2002).

Unexplained Chronic Diarrhea

  • In HIV infection, there are many possible causes of diarrhea, including common bacterial (Salmonella, Shigella, Listeria, Campylobacter, or Escherichia coli) and parasitic infections, and uncommon opportunistic infections such as cryptosporidiosis, microsporidiosis, Mycobacterium avium complex (MAC) and cytomegalovirus (CMV) colitis.
  • Diarrhea may follow a course of antibiotics (common for Clostridium difficile). It may also be a side effect of several drugs used to treat HIV, or it may simply accompany HIV infection, particularly during primary HIV infection. In the later stages of HIV infection, diarrhea is thought to be a reflection of changes in the way the intestinal tract absorbs nutrients, and may be an important component of HIV-related wasting (Guerrant et al., 1990).

C. The Major Neurological Illnesses

Toxoplasmosis

Toxoplasmosis of heart in AIDS
  • Toxoplasmosis is a disease caused by the single-celled parasite called Toxoplasma gondii. T. gondii usually infects the brain causing toxoplasma encephalitis. It can also infect and cause disease in the eyes and lungs (Luft and Chua, 2000).

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease, in which the myelin sheath covering the axons of nerve cells is gradually destroyed, impairing the transmission of nerve impulses. It is caused by a virus called JC virus which occurs in 70% of the population in latent form, causing disease only when the immune system has been severly weakened, as is the case for AIDS patients. It progresses rapidly, usually causing death within months of diagnosis (Sadler and Nelson, 1997).

HIV-associated Dementia

HIV-1 associated dementia (HAD) is a metabolic encephalopathy induced by HIV infection and fueled by immune activation of brain macrophages and microglia (Gray et al., 2001). These cells are actively infected with HIV and secrete neurotoxins of both host and viral origin. Specific neurologic impairments are manifested by cognitive, behavioral, and motor abnormalities that occur after years of HIV infection and is associated with low CD4+ T cell levels and high plasma viral loads. Prevalence is between 15-30% in Western countries (Heaton et al., 1995; White et al., 1995) and has only been seen in 1-2% of India based infections (Satischandra et al., 2000; Wadia et al., 2001).

D. HIV-associated malignancies

Patients with HIV infection are susceptible to a number of malignancies (Yarchoan et al., 2005). The most common is Kaposi's sarcoma, and the appearance of this tumor in young gay men in New York in 1981 was one of the first signals of the AIDS epidemic. In addition, patients with HIV infection have a higher incidence of certain high grade B cell lymphomas, especially Burkitt-like and large cell lymphomas. These tumors, as well as aggressive cervical cancer in women, confer a diagnosis of AIDS in patients with HIV infection. AIDS-related lymphoma describes lymphomas occurring in patients with acquired immunodeficiency syndrome (AIDS).

A lymphoma is a type of cancer arising from lymphoid cells. In AIDS, the incidences of non-Hodgkin's lymphoma, primary cerebral lymphoma and Hodgkin's disease are all increased.

Non-Hodgkin's Lymphoma

Non-Hodgkin's lymphoma (NHL) is present in about 3% of HIV positive people at the time of their diagnosis of HIV. 20% of HIV positive patients will develop NHL.

Primary Cerebral Lymphoma

Primary cerebral lymphoma (or primary central nervous system lymphoma) is a form of NHL. It is very rare in immunocompetent people, with an incidence of 5-30 cases per million person-years. However the incidence in immunocompromised individuals is greatly increased, up to 100 per million person-years.

Primary cerebral lymphoma is strongly associated with Epstein-Barr virus (EBV). The presence of EBV DNA in cerebrospinal fluid is highly suggestive of primary cerebral lymphoma.

Treatment of AIDS patients with antiretroviral drugs reduces the incidence of primary cerebral lymphoma.

Hodgkin's Disease

The incidence of Hodgkin's disease in the general population is about 10-30 per million person-years. This increases to 170 per million person-years in HIV positive patients.

E. The Major Dermatological illnesses

AIDS-associated Kaposi sarcoma or KS-AIDS presents with cutaneous lesions that begin as one or several red to purple-red macules, rapidly progressing to papules, nodules, and plaques, with a predilection for the head, neck, trunk, and mucous membranes.


  • Kaposi's sarcoma lesion commonly found in patients with stage IV AIDS

    Kaposi's sarcoma lesion commonly found in patients with stage IV AIDS

  • Intraoral Kaposi’s sarcoma lesion with an overlying candidiasis infection

    Intraoral Kaposi’s sarcoma lesion with an overlying candidiasis infection

HIV transmission

Estimated risk for acquisition of HIV-1 by exposure route[11]
Exposure Route Estimated infections
per 10,000 exposures
to an infected source
Blood Transfusion 9,000[12]
Childbirth 2,500[13]
Needle-sharing injection drug use 67[14]
Receptive anal intercourse 50[15][16]
Percutaneous needle stick 30[17]
Receptive penile-vaginal intercourse 10[15][16][18]
Insertive anal intercourse 6.5[15][16]
Insertive penile-vaginal intercourse 5[15][16]
Receptive fellatio 1[16]
Insertive fellatio 0.5[16]
Assuming no condom use.

Since the beginning of the pandemic, three main transmission routes for HIV have been identified:

  • Sexual route. The majority of HIV infections are acquired through unprotected sexual relations. Sexual transmission can occur when infected sexual secretions of one partner come into contact with the genital, oral, or rectal mucous membranes of another.
  • Blood or blood product route. This transmission route can account for infections in intravenous drug users, hemophiliacs and recipients of blood transfusions (though most transfusions are checked for HIV in the developed world) and blood products. It is also of concern for persons receiving medical care in regions where there is prevalent substandard hygiene in the use of injection equipment, such as the reuse of needles in Third World countries. HIV can also be spread through the sharing of needles. Health care workers such as nurses, laboratory workers, and doctors, have also been infected, although this occurs more rarely. People who give and receive tattoos, piercings, and scarification procedures can also be at risk of infection.
  • Mother-to-child transmission (MTCT). The transmission of the virus from the mother to the child can occur in utero during pregnancy and intrapartum at childbirth. In the absence of treatment, the transmission rate between the mother and child is around 25%.[13] However, where combination antiretroviral drug treatment and Cesarian section are available, this risk can be reduced to as low as 1%.[13] Breast feeding also presents a risk of infection for the baby.
  • HIV-2 is transmitted much less frequently by the MTCT and sexual route than HIV-1.
  • HIV has been found at low concentrations in the saliva, tears and urine of infected individuals, but there are no recorded cases of infection by these secretions and the potential risk of transmission is negligible.[19]
  • The use of physical barriers such as the latex condom is widely advocated to reduce the sexual transmission of HIV. Spermicide, when used alone or with vaginal contraceptives like a diaphragm, actually increases the male to female transmission rate due to inflammation of the vagina; it should not be considered a barrier to infection.[20]
  • A panel of experts convened by WHO and the UNAIDS Secretariat has "recommended that male circumcision now be recognized as an additional important intervention to reduce the risk of heterosexually acquired HIV infection in men."[21]
  • Research is clarifying whether there is a historical relationship between rates of male circumcision and rates of HIV in differing social and cultural contexts. Previously, Siegfried et al. suggested that it was possible that the correlation between circumcision and HIV in observational studies may be due to confounding factors, and remarked that the randomised controlled trials would therefore provide "essential evidence" about the effects of circumcision.[22]
  • There is little data on circumcision's effect on HIV risk with homosexual men and it is still being studied. A study of foreign and American men by scientists at the University of Washington, Seattle concluded: "Uncircumcised homosexual men in Seattle had a two fold increased risk of HIV infection.
  • If the relative risk that we observed in Seattle were also present in other populations, the population attributable risk of uncircumcised status for HIV in homosexual men would be 40%, i.e., 40% of homosexual transmission of HIV could be potentially preventable with universal circumcision."[4]
  • A study of Australian men headed by David Templeton, MD, from the University of New South Wales found "no relationship at all between circumcision and HIV seroconversion in" homosexual men. Templeton theorizes that this may be because most HIV occurs "following receptive rather than insertive intercourse," as he finds data on circumcision's effect on heterosexual men "compelling".[5] South African medical experts are concerned that the repeated use of unsterilized blades in the ritual (not medical) circumcision of adolescent boys may be spreading HIV.[23]
See also: Criminal transmission of HIV

Classification/Types of HIV microbe

  • Two species of HIV infect humans: HIV-1 and HIV-2. HIV-1 is thought to have originated in southern Cameroon after jumping from wild chimpanzees (Pan troglodytes troglodytes) to humans during the twentieth century.[24][25]
  • HIV-1 is the virus that was initially discovered and termed LAV. It is more virulent and relatively easy transmitted and is the cause of the majority of HIV infections globally. HIV-2 may have originated from the Sooty Mangabey (Cercocebus atys), an Old World monkey of Guinea-Bissau, Gabon, and Cameroon.[26]
  • HIV-2 is less transmittable than HIV-1 and is largely confined to West Africa.[26]

AIDS-related complex

Definition

ARC is "A prodromal phase of effects phase of infection with the human immunodeficiency virus ( HIV). Laboratory criteria separating AIDS-related complex ( ARC) from AIDS include elevated or hyperactive B-cell humoral immune responses, compared to depressed or normal antibody reactivity in AIDS; follicular or mixed hyperplasia in ARC lymph nodes, leading to lymphocyte degeneration and depletion more typical of AIDS; evolving succession of histopathological lesions such as localization of Kaposi's sarcoma, signaling the transition to the AIDS.[27]

References

  1. ↑ Guss DA (1994). "The acquired immune deficiency syndrome: an overview for the emergency physician, Part 1". J Emerg Med. 12 (3): 375–84. PMID 8040596. |access-date= requires |url= (help)
  2. ↑ Frazer IH, Mackay IR, Crapper RM, Jones B, Gust ID, Sarngadharan MG, Campbell DC, Ungar B (1986). "Immunological abnormalities in asymptomatic homosexual men: correlation with antibody to HTLV-III and sequential changes over two years". Q. J. Med. 61 (234): 921–33. PMID 3498182. Retrieved 2012-05-24. Unknown parameter |month= ignored (help)
  3. ↑ Schechter MT, Boyko WJ, Craib KJ, McLeod A, Willoughby B, Douglas B, Constance P, O'Shaughnessey M (1987). "Effects of long-term seropositivity to human immunodeficiency virus in a cohort of homosexual men". AIDS. 1 (2): 77–82. PMID 2966631. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  4. ↑ Moir S, Malaspina A, Pickeral OK, Donoghue ET, Vasquez J, Miller NJ, Krishnan SR, Planta MA, Turney JF, Justement JS, Kottilil S, Dybul M, Mican JM, Kovacs C, Chun TW, Birse CE, Fauci AS (2004). "Decreased survival of B cells of HIV-viremic patients mediated by altered expression of receptors of the TNF superfamily". J. Exp. Med. 200 (7): 587–99. PMID 15508184. Retrieved 2012-05-25. Unknown parameter |month= ignored (help)
  5. ↑ Moir S, Malaspina A, Ogwaro KM, Donoghue ET, Hallahan CW, Ehler LA, Liu S, Adelsberger J, Lapointe R, Hwu P, Baseler M, Orenstein JM, Chun TW, Mican JA, Fauci AS (2001). "HIV-1 induces phenotypic and functional perturbations of B cells in chronically infected individuals". Proc. Natl. Acad. Sci. U.S.A. 98 (18): 10362–7. doi:10.1073/pnas.181347898. PMC 56966. PMID 11504927. Retrieved 2012-05-25. Unknown parameter |month= ignored (help)
  6. ↑ Talal AH, Irwin CE, Dieterich DT, Yee H, Zhang L (2001). "Effect of HIV-1 infection on lymphocyte proliferation in gut-associated lymphoid tissue". J. Acquir. Immune Defic. Syndr. 26 (3): 208–17. PMID 11242193. Retrieved 2012-05-25. Unknown parameter |month= ignored (help)
  7. ↑ Poles MA, Boscardin WJ, Elliott J, Taing P, Fuerst MM, McGowan I, Brown S, Anton PA (2006). "Lack of decay of HIV-1 in gut-associated lymphoid tissue reservoirs in maximally suppressed individuals". J. Acquir. Immune Defic. Syndr. 43 (1): 65–8. doi:10.1097/01.qai.0000230524.71717.14. PMID 16936559. Retrieved 2012-05-25. Unknown parameter |month= ignored (help)
  8. ↑ Guadalupe M, Reay E, Sankaran S, Prindiville T, Flamm J, McNeil A, Dandekar S (2003). "Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy". J. Virol. 77 (21): 11708–17. PMC 229357. PMID 14557656. Retrieved 2012-05-25. Unknown parameter |month= ignored (help)
  9. ↑ Shacklett BL, Cox CA, Sandberg JK, Stollman NH, Jacobson MA, Nixon DF (2003). "Trafficking of human immunodeficiency virus type 1-specific CD8+ T cells to gut-associated lymphoid tissue during chronic infection". J. Virol. 77 (10): 5621–31. PMC 154016. PMID 12719554. Retrieved 2012-05-25. Unknown parameter |month= ignored (help)
  10. ↑ Jones JL, Hanson DL, Dworkin MS, Alderton DL, Fleming PL, Kaplan JE, Ward J (1999). "Surveillance for AIDS-defining opportunistic illnesses, 1992-1997". MMWR CDC Surveill Summ. 48 (2): 1–22. PMID 12412613. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  11. ↑ Smith, D. K., Grohskopf, L. A., Black, R. J., Auerbach, J. D., Veronese, F., Struble, K. A., Cheever, L., Johnson, M., Paxton, L. A., Onorato, I. A. and Greenberg, A. E. (2005). "Antiretroviral Postexposure Prophylaxis After Sexual, Injection-Drug Use, or Other Nonoccupational Exposure to HIV in the United States". MMWR. 54 (RR02): 1–20.
  12. ↑ Donegan, E., Stuart, M., Niland, J. C., Sacks, H. S., Azen, S. P., Dietrich, S. L., Faucett, C., Fletcher, M. A., Kleinman, S. H., Operskalski, E. A.; et al. (1990). "Infection with human immunodeficiency virus type 1 (HIV-1) among recipients of antibody-positive blood donations". Ann. Intern. Med. 113 (10): 733–739. PMID 2240875.
  13. ↑ 13.0 13.1 13.2 Coovadia, H. (2004). "Antiretroviral agents—how best to protect infants from HIV and save their mothers from AIDS". N. Engl. J. Med. 351 (3): 289–292. PMID 15247337.
  14. ↑ Kaplan, E. H. and Heimer, R. (1995). "HIV incidence among New Haven needle exchange participants: updated estimates from syringe tracking and testing data". J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 10 (2): 175–176. PMID 7552482.
  15. ↑ 15.0 15.1 15.2 15.3 European Study Group on Heterosexual Transmission of HIV (1992). "Comparison of female to male and male to female transmission of HIV in 563 stable couples". BMJ. 304 (6830): 809–813. PMID 1392708.
  16. ↑ 16.0 16.1 16.2 16.3 16.4 16.5 Varghese, B., Maher, J. E., Peterman, T. A., Branson, B. M. and Steketee, R. W. (2002). "Reducing the risk of sexual HIV transmission: quantifying the per-act risk for HIV on the basis of choice of partner, sex act, and condom use". Sex. Transm. Dis. 29 (1): 38–43. PMID 11773877.
  17. ↑ Bell, D. M. (1997). "Occupational risk of human immunodeficiency virus infection in healthcare workers: an overview". Am. J. Med. 102 (5B): 9–15. PMID 9845490.
  18. ↑ Leynaert, B., Downs, A. M. and de Vincenzi, I. (1998). "Heterosexual transmission of human immunodeficiency virus: variability of infectivity throughout the course of infection. European Study Group on Heterosexual Transmission of HIV". Am. J. Epidemiol. 148 (1): 88–96. PMID 9663408.
  19. ↑ Lifson AR (1988). "Do alternate modes for transmission of human immunodeficiency virus exist? A review". JAMA. 259 (9): 1353–6. PMID 2963151.
  20. ↑ "Should spermicides be used with condoms?". Condom Brochure, FDA OSHI HIV STDs. Retrieved 2006-10-23.
  21. ↑ WHO (2007). "WHO and UNAIDS announce recommendations from expert consultation on male circumcision for HIV prevention". WHO.int. Retrieved 2007-07-13.
  22. ↑ Siegfried, N., Muller, M., Deeks, J., Volmink, J., Egger, M., Low, N., Walker, S. and Williamson, P. (2005). "HIV and male circumcision--a systematic review with assessment of the quality of studies". Lancet Infect. Dis. 5 (3): 165–173. PMID 15766651.
  23. ↑ Various (2005). "Repeated Use of Unsterilized Blades in Ritual Circumcision Might Contribute to HIV Spread in S. Africa, Doctors Say". Kaisernetwork.org. Retrieved 2006-03-28.
  24. ↑ Gao, F., Bailes, E., Robertson, D. L., Chen, Y., Rodenburg, C. M., Michael, S. F., Cummins, L. B., Arthur, L. O., Peeters, M., Shaw, G. M., Sharp, P. M., and Hahn, B. H. (1999). "Origin of HIV-1 in the Chimpanzee Pan troglodytes troglodytes". Nature. 397 (6718): 436–441. doi:10.1038/17130. PMID 9989410.
  25. ↑ Keele, B. F., van Heuverswyn, F., Li, Y. Y., Bailes, E., Takehisa, J., Santiago, M. L., Bibollet-Ruche, F., Chen, Y., Wain, L. V., Liegois, F., Loul, S., Mpoudi Ngole, E., Bienvenue, Y., Delaporte, E., Brookfield, J. F. Y., Sharp, P. M., Shaw, G. M., Peeters, M., and Hahn, B. H. (2006). "Chimpanzee Reservoirs of Pandemic and Nonpandemic HIV-1". Science. Online 2006-05-25. doi:10.1126/science.1126531.
  26. ↑ 26.0 26.1 Reeves, J. D. and Doms, R. W (2002). "Human Immunodeficiency Virus Type 2". J. Gen. Virol. 83 (Pt 6): 1253–1265. PMID 12029140.
  27. ↑ As listed by the National Library of Medicine under Medical Subject Headings


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