HIV disease progression rates
Following infection with HIV-1, the rate of clinical disease progression varies between individuals. Factors such as host susceptibility, genetics and immune function (Morgan et al., 2002b), health care and co-infections (Morgan et al., 2002a) as well as viral genetic variability (Campbell et al., 2004) may affect the rate of progression to AIDS.
Additional recommended knowledge
A small percentage of HIV-infected individuals rapidly progress to AIDS within four years after primary HIV-infection and are termed Rapid Progressors (RP) (Anzala et al., 1995). Indeed some individuals have been known to progress to AIDS and death within a year after primo-infection. Rapid progression was originally thought to be continent specific, as some studies reported that disease progression is more rapid in Africa (N'Galy et al., 1988; Anzala et al., 1995; Whittle et al., 1992), but others have contested this view (Marlink et a., 1994; French et al., 1999; Morgan et al., 2002).
Long term non-progressors
Another subset of individuals who are persistently infected with HIV-1, but show no signs of disease progression for over 12 years and remain asymptomatic are classified as Long Term Non-Progressors (LTNP). In these individuals, it seems that HIV-infection has been halted with regard to disease progression over an extended period of time (Buchbinder et al., 1994; Cao et al., 1995; Easterbrook, 1994; Levy, 1993). However, the term LTNP is a misnomer, as it must be noted that progression towards AIDS can occur even after 15 years of stable infection (Harrer et al., 1996). LTNP are not a homogeneous group regarding both viral load and specific immune responses against HIV-1. Some LTNPs are infected with HIV that inefficiently replicates (Deacon et al., 1995; Kirchhoff et al., 1995) whilst others are infected with HIV that is virally fit and replicates normally, but the infected individual has had a strong and broad set of HIV-specific humoral and cell-mediated responses that seems to delay the progression to AIDS. In some cohorts, individuals who experience signs of progression, but whose clinical and laboratory parameters remain stable over long periods of time, are classified as Long Term Survivors (LTS) (Schrager et al., 1994; Campbell et al., 2004).
Highly exposed persistently seronegative
There is another, smaller percentage of individuals who have been recently identified. These are called Highly Exposed Persistently Seronegative (HEPS). This is a small group of individuals and has been observed only in a group of uninfected HIV-negative prostitutes in Kenya and in The Gambia. When these individuals' PBMCs are stimulated with HIV-1 peptides, they have lymphoproliferative activity and have HIV-1 specific CD8+ CTL activity suggesting that transient infection may have occurred (Clerici et al., 1994; Pinto et al., 1995; Rowland-Jones et al., 1995; Fowke et al., 1996). This does not occur in unexposed individuals. What is interesting, is that the CTL epitope specificity differs between HEPS and HIV positive individuals, and in HEPS, the maintenance of responses appears to be dependent upon persistent exposure to HIV (Kaul et al., 2001).
Prediction of progression rates
During the initial weeks after HIV infection, qualitative differences in the cell-mediated immune response are observed that correlate with different disease progression rates (i.e., rapid progression to WHO stage 4 and the rapid loss of CD4+ T cell levels versus normal to slow progression to WHO stage 4 and the maintenance of CD4+ T cell counts above 500/µl). The appearance of HIV-1-specific CD8+ cytotoxic T cells (CTLs) early after primo-infection has been correlated with the control of HIV-1 viremia (Koup et al., 1994; Borrow et al., 1994). The virus which escapes this CTL response have been found to have mutations in specific CTL epitopes (Philips et al., 1991; Borrow et al., 1997; Price et al., 1997; Rowland-Jones et al., 1992). Individuals with a broad expansion of the V-beta chain of the T cell receptor of CD8+ T cells during primo-infection appear seem to have low levels of virus six to twelve months later, which is predictive of relatively slow disease progression. In contrast, individuals with an expansion of only a single subset of the V-beta chain of the CD8+ T cells are not able to control HIV levels over time, and thus have high levels of virus six to twelve months later (Pantaleo et al., 1997). LTNP’s have also been shown to have a vigorous proliferation of circulating activated HIV-1-specific CD4+ T cell (Rosenberg et al., 1997) and CTL response (Rowland–Jones et al., 1999; Dyer et al., 1999) against multiple epitopes with no detectable broadly cross-reactive neutralizing antibodies in the setting of an extremely low viral load (Harrer et al., 1996). However, a few reports have correlated the presence of antibodies against Tat in LTNP status.
HIV subtype variation and effect on progression rates
The HIV-1 subtype that an individual becomes infected with can be a major factor in the rate of progression from sero-conversion to AIDS. Individuals infected with subtypes C, D and G are 8 times more likely to develop AIDS than individuals infected with subtype A (Kanki et al., 1999). In Uganda, where subtypes A and D are most prevalent (Kaleebu et al., 2000), subtype D is associated with faster disease progression compared with subtype A (Kaleebu et al., 2002). Age has also been shown to be a major factor in determining survival and the rate of disease progression, with individuals over 40 years of age at sero-conversion being associated with rapid progression (Koblin et al., 1999; Pezotti et al., 1999; Collaborative Group, 2000; Morgan et al., 2002b).
Host genetic susceptibility
The Centers for Disease Control and Prevention (CDC) has released findings that genes influence susceptibility to HIV infection and progression to AIDS. HIV enters cells through an interaction with both CD4 and a chemokine receptor of the 7 Tm family. They first reviewed the role of genes in encoding chemokine receptors (CCR5 and CCR2) and chemokines (SDF-1). While CCR5 has multiple variants in its coding region, the deletion of a 32-bp segment results in a nonfunctional receptor, thus preventing HIV entry; two copies of this gene provide strong protection against HIV infection, although the protection is not absolute. This gene is found in up to 20% of Europeans but is rare in Africans and Asians. Multiple studies of HIV-infected persons have shown that presence of one copy of this gene delays progression to the condition of AIDS by about 2 years. And it is possible that a person with the CCR5-Δ32 (CCR5 delta 32) receptor gene will not be infected with HIV.
The National Institute of Health (NIH) has funded research studies to learn more about this genetic mutation. In such research, NIH has found that there exist genetic tests that can determine if a person has this mutation. Implications of a genetic test may in the future allow clinicians to change treatment for the HIV infection according to the genetic makeup of an individual (Gonzalez et al). Currently there exists an at-home test, administered by HIVmirror. This test tests for the CCR5 mutation in individuals; however, this is not a diagnostic test.
A relatively new class of drugs for HIV treatment relies on the genetic makeup of the individual. Entry inhibitors bind to the CCR5 protein to block HIV from binding to the CD4 cell.
The effect of co-infections on progression rates
Coinfections or immunizations may enhance viral replication by inducing a response and activation of the immune system. This activation facilitates the three key stages of the viral life cycle: entry to the cell; reverse transcription and proviral transcription (Lawn et al., 2001). Chemokine receptors are vital for the entry of HIV into cells. The expression of these receptors is inducible by immune activation caused through infection or immunization, thus augmenting the number of cells that are able to be infected by HIV-1 (Wahl et al., 1998; Juffermans et al., 2001). Both reverse transcription of the HIV-1 genome and the rate of transcription of proviral DNA rely upon the activation state of the cell and are less likely to be successful in quiescent cells. In activated cells there is an increase in the cytoplasmic concentrations of mediators required for reverse transcription of the HIV genome (Zack et al., 1990; Kinoshita et al., 1998). Activated cells also release IFN-alpha which acts on an autocrine and paracrine loop that up-regulates the levels of physiologically active NF-kappa B which activates host cell genes as well as the HIV-1 LTR (Gaynor, 1992; Baeuerle, 1991). The impact of co-infections by micro-organisms such as Mycobacterium tuberculosis can be important in disease progression, particularly for those who have a high prevalence of chronic and recurrent acute infections and poor access to medical care (Blanchard et al., 1997). Often, survival depends upon the initial AIDS-defining illness (Morgan et al., 1997). Co-infection with DNA viruses such as HTLV-1, herpes simplex virus-2, varicella zoster virus and cytomegalovirus may enhance proviral DNA transcription and thus viral load as they may encode proteins that are able to trans-activate the expression of the HIV-1 pro-viral DNA (Gendelman et al., 1986). Frequent exposure to helminth infections, which are endemic in Africa, activates individual immune systems, thereby shifting the cytokine balance away from an initial Th1 cell response against viruses and bacteria which would occur in the uninfected person to a less protective T helper 0/2-type response (Bentwich et al., 1995). HIV-1 also promotes a Th1 to Th0 shift and replicates preferentially in Th2 and Th0 cells (Maggi et al., 1994). This makes the host more susceptible to and less able to cope with infection with HIV-1,viruses and some types of bacteria
- All references below may be found on Entrez, a life sciences information search engine provided by the US National Center for Biotechnology Information.
- Anzala, O. A., Nagelkerke, N. J., Bwayo, J. J., Holton, D., Moses, S., Ngugi, E. N., Ndinya-Achola, J. O. and Plummer, F. A. (1995) Rapid progression to disease in African sex-workers with human immunodeficiency virus type 1 infection. J. Infect. Dis. 171, 686-689
- Baeuerle, P. A. (1991) The inducible transcription activator NF-kappaB: regulation by distinct protein subunits. Biochim. Biophys. Acta. 1072, 63-80
- Bentwich, Z., Kalinkovich., A. and Weisman, Z. (1995) Immune activation is a dominant factor in the pathogenesis of African AIDS. Immunol. Today 16, 187-191
- Blanchard, A., Montagnier, L. and Gougeon, M. L. (1997) Influence of microbial infections on the progression of HIV disease. Trends. Microbiol. 16, 326-331
- Borrow, P., Lewicki, H., Hahn, B. H., Shaw, G. M. and Oldstone, M. B. (1994) Virus- specific CD8+ cytotoxic T- lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J. Virol. 68, 6103–10
- Borrow, P., Lewicki, H., Wei, X., Horwitz, M. S., Peffer, N., Meyers, H., Nelson, J. A., Gairin, J. E., Hahn, B.H., Oldstone, M. B. and Shaw, G. M. (1997) Antiviral pressure exerted by HIV- 1- specific cytotoxic T cells (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat. Med. 3, 205– 11
- Buchbinder, S. P., Katz, M. H., Hessol, N. A., O'Malley, P. M. and Holmberg, S. D. (1994) Long-term HIV-1 infection without immunologic progression. AIDS 8, 1123-1128
- Campbell, G. R., Pasquier, E., Watkins, J., Bourgarel-Rey, V., Peyrot, V., Esquieu, D., Barbier, P., de Mareuil, J., Braguer, D., Kaleebu, P., Yirrell, D. L. and Loret, E. P. (2004) The glutamine-rich region of HIV-1 Tat protein involved in T cell apoptosis. J. Biol. Chem. 279, 48197-48204
- Cao Y., Qin, L., Zhang, L., Safrit, J. and Ho, D. D. (1995) Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N. Engl. J. Med. 332, 201-208
- Clerici, M., Levin, J. M., Kessler, H. A., Harris, A., Berzofsky, J. A., Landay, A. L. and Shearer, G. M. (1994) HIV- specific T- helper activity in seronegative health care workers exposed to contaminated blood. JAMA 271, 42–46
- Collaborative Group on AIDS Incubation and HIV Survival including the CASCADE EU Concerted Action. Concerted Action on SeroConversion to AIDS and Death in Europe. (2000) Time from HIV-1 seroconversion to AIDS and death before widespread use of highly active antiretroviral therapy: a collaborative re-analysis. Lancet 355, 1131-1137
- Deacon NJ, Tsykin A, Solomon A, Smith K, Ludford-Menting M, Hooker DJ, McPhee DA, Greenway AL, Ellett A, Chatfield C., Lawson, V. A., Crowe, S., Maerz, A., Sonza, S., Learmont, J., Sullivan, J. S., Cunningham, A., Dwyer, D., Dowton, D. and Mills, J. (1995) Genomic structure of an attenuated quasi species of HIV-1 from a blood transfusion donor and recipients. Science 270, 988-991
- Dyer, W. B., Ogg, G. S., Menoitie, M. A., Jin, X., Geczy, A. F., Rowland- Jones, S. L., McMichael, A. Nixonn, J. and Sullivan, D. F. (1999) Strong human immunodeficiency virus (HIV)- specific cytotoxic T- lymphocytes activity in Sydney Blood Bank Cohort patients infected with nef- defective HIV- type 1. J. Virol. 73, 436– 443
- Easterbrook, P. J. (1994) Non-progression in HIV infection. AIDS 8, 1179-1182
- Fowke, K. R., Nagelkerke, N. J., Kimani, J., Simonsen, J. N., Anzala, A. O., Bwayo, J. J., MacDonald, K. S., Ngug, E. N. and Plummer, F. A. (1996) Resistance to HIV- 1 infection among persistently seronegative prostitutes in Nairobi, Kenya. Lancet 348, 1347– 1351
- French, N., Mujugira, A., Nakiyingi, J., Mulder, D., Janoff, E. N. and Gilks, C. F. (1999) Immunologic and clinical stages in HIV-1-infected Ugandan adults are comparable and provide no evidence of rapid progression but poor survival with advanced disease. J. Acquir Immune Defic. Syndr. 22, 509-516
- Gaynor, R. (1992) Cellular transcription factorsinvolved in the regulation of HIV-1 gene expression. AIDS 6, 347-363
- Gendelman, H. E., Phelps, W., Feigenbaum, L., Ostrove, J. M., Adachi, A., Howley, P. M., Khoury, G., Ginsberg, H. S. and Martin, M. A. (1986) Transactivation of the human immunodeficiency virus long terminal repeat sequences by DNA viruses. Proc. Natl. Acad. Sci. U. S. A. 83, 9759-9763
- Gonzalez et al. The influence of CCL3L1 gene-containing segmental duplications on HIV-1/AIDS susceptibility. Science DOI: 10.1126/science.1101160.
- Harrer, T., Harrer, E., Kalams, S. A., Elbeik, T., Staprans, S. I., Feinberg, M. B., Cao, Y., Ho, D. D., Yilma, T., Caliendo, A. M., Johnson, R. P., Buchbinder, S. P. and Walker, B. D. (1996) Strong cytotoxic T cell and weak neutralizing antibody responses in a subset of persons with stable nonprogressing HIV type 1 infection. AIDS Res. Hum. Retroviruses. 12, 585-592
- Juffermans, N. P., Speelman, P., Verbon, A., Veenstra, J., Jie, C., van Deventer, S. J. and van Der Poll, T. (2001) Patients with active tuberculosis have increased expression of HIV coreceptors CXCR4 and CCR5 on CD4(+) T cells. Clin. Infect. Dis. 32, 650-652
- Kaleebu, P., Whitworth, J., Hamilton, L., Rutebemberwa, A., Lyagoba, F., Morgan, D., Duffield, M., Biryahwaho, B., Magambo, B. and Oram, J. (2000) Molecular epidemiology of HIV type 1 in a rural community in southwest Uganda. AIDS Res. Hum. Retroviruses. 16, 393-401
- Kaleebu, P., French, N., Mahe, C., Yirrell, D., Watera, C., Lyagoba, F., Nakiyingi, J., Rutebemberwa, A., Morgan, D., Weber, J., Gilks, C. and Whitworth, J. (2002) Effect of human immunodeficiency virus (HIV) type 1 envelope subtypes A and D on disease progression in a large cohort of HIV-1-positive persons in Uganda. J. Infect. Dis. 185, 1244-1250
- Kanki, P. J., Hamel, D. J., Sankale, J. L., Hsieh, C., Thior, I., Barin, F., Woodcock, S. A., Gueye-Ndiaye, A., Zhang, E., Montano, M., Siby, T., Marlink, R., Ndoye, I., Essex, M. E. and Mboup, S. (1999) Human immunodeficiency virus type 1 subtypes differ in disease progression. J. Infect. Dis. 179, 68-73
- Kaul, R., Rowland-Jones, S. L., Kimani, J., Fowke, K., Dong, T., Kiama, P., Rutherford, J., Njagi, E., Mwangi, F., Rostron, T., Onyango, J., Oyugi, J., MacDonald, K., S., Bwayo, J., J. and Plummer, F. A. (2001) New insights into HIV-1 specific cytotoxic T cell responses in exposed, persistently seronegative Kenyan sex workers. Immunol. Letts. 79, 3-13
- Kinoshita, S., Chen, B. K., Kaneshima, H. and Nolan, G. P. (1998) Host control of HIV-1 parasitism in T cells by the nuclear factor of activated T cells. Cell 95, 595-604
- Kirchhoff, F., Greenough, T. C., Brettler, D. B., Sullivan, J. L. and Desrosiers, R. C. (1995) Brief report: absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. N. Engl. J. Med. 332, 228-232
- Koblin, B. A., van Benthem, B. H., Buchbinder, S. P., Ren, L., Vittinghoff, E., Stevens, C. E., Coutinho, R. A. and van Griensven, G. J. (1999) Long-term survival after infection with human immunodeficiency virus type 1 (HIV-1) among homosexual men in hepatitis B vaccine trial cohorts in Amsterdam, New York City, and San Francisco, 1978-1995. Am. J. Epidemiol. 150, 1026-1030
- Koup, R. A., Safrit, J. T. and Cao, Y. Z. (1994) Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J. Virol. 68, 4650– 4655
- Lawn, S. D., Butera, S. T. and Folks, T. M. (2001) Contribution of immune activation to the pathogenesis and transmissionof human immunodeficiency virus type 1 infection. Clin. Microbiol. Rev. 14, 753-777
- Lévy, J. A. (1993) HIV pathogenesis and long-term survival. AIDS 7, 1401-1410
- Maggi, E., Mazzetti, M., Ravina, A., Annunziato, F., de Carli, M., Piccinni, M. P., Manetti, R., Carbonari, M., Pesce, A. M., del Prete, G. F. and Romagnani, S. (1994) Ability of HIV to promote a Th1 to Th0 shift and to replicate preferentially in Th2 and Th0 cells. Science 265, 244-248
- Marlink, R., Kanki, P., Thior, I., Travers, K., Eisen, G., Siby, T., Traoré, I., Hsieh, C-C., Dia, M. C., Gueye, E. H., Hellinger, J., Gueye-Ndiaye, A., Sankalé, J-L., Ndoye, I., Mboup, S. and Essex, M. (1994) Reduced rate of disease development after HIV-2 infection as compared to HIV-1. Science 265, 1587-1590
- Morgan, D., Maude, G. H., Malamba, S. S., Okongo, M. J., Wagner, H. U., Mulder, D. W. and Whitworth, J. A. (1997) HIV-1 disease progression and AIDS-defining disorders in rural Uganda. Lancet 350, 245-250
- Morgan, D., Mahe, C., Mayanja, B. and Whitworth, J. A. (2002a) Progression to symptomatic disease in people infected with HIV-1 in rural Uganda: prospective cohort study. BMJ 324, 193-196
- Morgan, D., Mahe, C., Mayanja, B., Okongo, J. M., Lubega, R. and Whitworth, J. A. (2002b) HIV-1 infection in rural Africa: is there a difference in median time to AIDS and survival compared with that in industrialized countries? AIDS 16, 597-6032
- N'Galy, B., Ryder, R. W., Bila, K., Mwandagalirwa, K., Colebunders, R. L., Francis, H., Mann, J. M. and Quinn, T. C. (1988) Human immunodeficiency virus infection among employees in an African hospital. N. Eng. J. Med. 319, 1123-1127
- Pantaleo, G., Demarest, J. F., Schacker, T., Vaccarezza, M., Cohen, O.J., Daucher, M., Graziosi, C., Schnittman, S. S., Quinn, T. C., Shaw, G. M., Perrin, L., Tambussi, G., Lazzarin, A., Sekaly, R. P., Soudeyns, H., Corey, L. and Fauci, A. S. (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, 254-258
- Phillips, R. E., Rowland-Jones, S., Nixon, D. F., Gotch, F. M., Edwards, J. P., Ogunlesi, A. O., Elvin, J. G., Rothbard, J. A., Bangham, C. R., Rizza, C. R. and McMichael, A. J. (1991) Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature 354, 453-459
- Pinto, L. A., Sullivan, J., Berzofsky, J. A., Clerici, M., Kessler, H. A., Landay, A. L. and Shearer, G. M. (1995) ENV- specific cytotoxic T cell responses in HIV seronegative health care workers occupationally exposed to HIV- contaminated body fluids. J. Clin. Invest. 96, 867-876
- Price, D. A., Goulder, P. J., Klenerman, P., Sewell, A. K., Easterbrook, P. J., Troop, M., Bangham, C. R. and Phillips, R. E. (1997) Positive selection of HIV- 1 cytotoxic T cell escape variants during primary infection. Proc. Natl. Acad. Sci. U. S. A. 94, 1890-1895
- Rosenberg, E. S., Billingsley, J. M., Caliendo, A. M., Boswell, S. L., Sax, P. E., Kalams, S. A. and Walker, B. D. (1997) Vigorous HIV- 1- specific CD4+ T cell responses associated with control of viremia. Science 278, 1447-1450
- Rowland- Jones, S. L., Phillips, R. E., Nixon, D. F., Gotch, F. M., Edwards, J. P., Ogunlesi, A. O., Elvin, J. G., Rothbard, J. A., Bangham C. R., Rizza, C. R. and McMichael, A. J. (1992) Human immunodeficiency virus variants that escape cytotoxic T- cell recognition. AIDS Res. Hum. Retroviruses 8, 1353-1354
- Rowland- Jones, S., Sutton, J., Ariyoshi, K., Dong, T., Gotch, F., McAdam, S., Whitby, D., Sabally, S., Gallimore, A. and Corrah, T. (1995) HIV- specific cytotoxic T- cells in HIV- exposed but uninfected Gambian women. Nat. Med. 1, 59-64
- Rowland- Jones, S. L., Dong, T., Dorrell, L., Ogg, G., Hansasuta, P., Kra, P., Kimani, J., Sabally, S., Ariyoshi, K., Oyugi, J., MacDonald, K. S., Bwayo, J., Whittle, H., Plummer, F. A. and McMichael, A. J. (1999) Broadly cross- reactive HIV- specific cytotoxic T- lymphocytes in highly exposed persistently seronegative donors. Immunol. Lett. 66, 9-14
- Wahl, S. M., Greenwell-Wild, T., Peng, G., Hale-Donze, H., Doherty, T. M., Mizel, D. and Orenstein, J. M. (1998) Mycobacterium avium complex augments macrophage HIV-1 production and increases CCR5 expression. Proc. Natl. Acad. Sci. U. S. A. 95, 12574-12579
- Whittle, H., Egboga, A., Todd, J., Corrah, T., Wilkins, A., Demba, E., Morgan, G., Rolfe, M., Berry, N. and Tedder, R. (1992) Clinical and laboratory predictors of survival in Gambian patients with symptomatic HIV-1 or HIV-1 infection. AIDS 6, 685-689
- Zack, J. A., Arrigo, S. J., Weitsman, S. R., Go, A. S., Haislip, A. and Chen, I. S. (1990) HIV-1 entry into quiescent primary lymphocytes: milecular analysis reveals a labile, latent viral structure. Cell 61, 213-222