Myth: The fact that some HIV-positive people live in good health without treatment for many years proves that HIV is harmless

Fact: A small percentage of people infected with HIV do live for many years without developing AIDS. They are often known as long-term non-progressors. But such individuals are rare: without proper medical care, including antiretroviral drugs when needed, most HIV-positive people will eventually develop AIDS.

As putative evidence that HIV is harmless, some HIV/AIDS denialists point to examples of HIV-infected people who survive for many years, even decades, without receiving antiretroviral treatment. HIV denialists often claim that these people survived because they avoided antiretroviral therapy, and that diet, exercise, nutritional supplements or herbal therapies, stress reduction, hypnosis, and other interventions prevent progression to AIDS. These claims are untrue and dangerous.

It is true that a small number of people, often known by doctors and researchers as long-term non-progressors (LTNP), can survive with HIV and without treatment for prolonged periods (over 20 years in exceptional cases). Unfortunately, without careful monitoring and treatment, most HIV-infected people will develop AIDS within ten years of infection. Those who live longer without standard medical care are not always in good health, and some HIV-infected AIDS denialists (e.g., Christine Maggiore) have died of AIDS-related conditions just months after claiming to be healthy. Ignoring HIV infection, avoiding properly qualified doctors, or hoping that a healthy lifestyle will prevent disease indefinitely, will result in the unnecessarily early illness and death of the great majority of HIV-infected people.

Who are long-term non-progressors?

A small percentage of people infected with HIV do not experience the profound and sustained CD4+ T-cell depletion characteristic of HIV infection or develop AIDS-related illnesses for many years, even without treatment with antiretroviral drugs (1). Some infants who were infected with HIV before or at the time of their birth have now survived without treatment to become young adults, but again this fortunate outcome is rare.

Because LTNPs may not always know they are infected, their proportion within the total HIV-infected population is uncertain. The formal definition of an LTNP has also varied over the years, and between different research cohorts in different countries. In some cohorts, fewer than 1 or 2% (2) are LTNPs; other estimates, such as the first studies in the 1990s, reported a higher percentage, between 5 and 15% (1). Most LTNPs eventually do develop AIDS (3). For example, Kemal et al. described the case of a man who had normal CD4 counts for over 18 years before he eventually progressed to AIDS (4). Nevertheless, the factors that allow LTNPs to delay progression to AIDS are the subject of intense interest, research, and hope: understanding these factors could guide development of effective new treatments or even a vaccine (5, 6). Far from supporting AIDS denialism, many LTNPs have recognized their personal abilities to aid others with HIV, by making important contributions to research.

Most LTNPs do have a quantifiable and sometimes substantial plasma viral load, but a subset, known as virus controllers, do not. A plasma HIV load (“viremia”) of about 2000 copies per milliliter (mL) is considered to be an important threshold. Below this level, both progression to AIDS and the risk of transmission are greatly reduced (5). An HIV-positive individual who does not take HIV medications and maintains a viral load below the 2000 level for at least a year is considered a “viremic controller”; those who maintain a level under 50 copies per mL, the current limit of detection for most commercial tests, are called “elite controllers” (5). Elite controllers do not eradicate HIV infection—at least, no such cases have been conclusively demonstrated. Low-level viremia is still detectable in the majority of these elite controllers when one uses laboratory tests sensitive to less than one copy per mL of plasma (7). Nor are all elite controllers in perfect immunological health: very low levels of virus do not guarantee non-progression and are associated with slight but measurable declines in CD4+ T-cell levels (7, 8), and even elite controllers can sometimes progress to AIDS.

Why is there variation in disease progression rates in different people?

Virus and host genetics, not healthy living or avoiding antiretrovirals, explain the differences between those with a typical progression to AIDS and those who remain healthy for longer. There are many different strains of HIV. Some LTNPs are infected with poorly replicating or even defective strains of HIV. These variant viruses may be less infectious, less able to evade the immune system, or less harmful to host cells. For example, in the early 1980s, a strain of HIV defective in its Nef accessory gene spread from a single donor to six transfusion recipients in New South Wales, Australia. Nef is a protein that helps HIV both to replicate and to evade the immune system. Without it, the virus is less dangerous within infected people. As of 2008, three of these people were still living without AIDS and without antiviral treatments (“antiviral naïve”). The other three have died, but not of AIDS; in fact, only one person developed AIDS symptoms before death (9). Thus, much like antiretroviral therapy does in typical HIV cases (10), the defective virus has allowed its hosts to live several decades after infection…and to die of non-AIDS causes.

Host genetics are another reason for long-term non-progression. In evolutionary terms, HIV is a newcomer. The genetics-based tricks and techniques of the immune system that evolved over countless generations to force viruses like chicken pox and herpes into latency--and for the most part to keep them there--have not yet had time to develop against HIV and spread through the human gene pool. However, some fairly common gene variants may help to protect against HIV infection and progression to AIDS, whether by chance or because of similarities between HIV and other viruses previously encountered by the human immune system. No single gene variant explains all LTNPs. Instead, scientists think that an ensemble of genes may be responsible, varying from person to person (11, 12). Here are a few examples of the many gene categories that affect innate or adaptive immune system processes and that play a role in progression to AIDS (1, 11):

HIV co-receptors: HIV uses cell-surface proteins in addition to CD4 as “co-receptors” to gain entry to cells. One of these co-receptors, CCR5, exists in a truncated, defective form that HIV cannot use. A person with two copies (or “alleles”) of the mutant gene (a delta32 homozygote) is highly, but not absolutely, resistant to HIV infection, but this protection does not apply to a person with only one allele (a delta32 heterozygote). Delta32 heterozygotes progress more slowly to AIDS and death compared with people who have two normal CCR5 alleles. The high-profile case of an HIV-positive man with leukemia who was reported “functionally cured” of HIV underscores the importance of this CCR5 variant: after he received a bone marrow transplant from a CCR5-delta32 homozygous donor, doctors could no longer find HIV in his blood or in several tissues they examined (13). Although it remains to be seen if this man was truly cured of HIV infection, co-receptor variants clearly affect viral disease (some slow it down, others speed it up). Important alleles of related receptors and other proteins, including CCR2, CX3CR1, and CXCR1, have been reported also to affect disease progression rates (2).

HLA alleles: The human leukocyte antigens (HLAs) are cell-surface proteins that dangle pieces of chewed-up virus for the immune system to recognize. Several specific HLA alleles and genes for proteins that interact with them have been implicated in AIDS progression (1). People with the HLAB*57 or *27 alleles have slower progression; those with HLAB*35 progress faster (2).

Signaling: Signaling proteins known as cytokines/chemokines, for example IL-10, MIP1A, RANTES, CCL2 and SDF-1, are produced by the body to fight viral infection or control inflammation. Genetic variants in their genes or regulatory sequences affect how much of each protein is made and thereby influence disease progression.

Other innate immunity components: APOBEC: Members 3G and F of this protein family may accelerate the naturally high mutation rate of HIV to unsustainable levels. Genes or genetic sequences that affect the amount and activity of APOBEC could influence HIV progression. The antiviral protein TRIM5alpha slows down HIV after it enters the cell, keeping it from shedding its “coat” of capsid protein. Variants of Toll-like receptors (TLRs) 7/8 and 9 have also been reported to have an influence.

Genes that influence production of different antibody types and effectiveness of cellular responses to HIV are also likely to affect disease progression rates.

Conclusion

Disease progression rates are strongly influenced by viral and human genetic factors, and although a healthy lifestyle is very important, HIV-infected people with the best health habits can and do progress to AIDS. Seeing a doctor and getting proper treatment is essential, even for LTNPs. It is important to remember that antiretroviral treatment does not cause AIDS. In fact, most HIV-infected people with access to these medications live longer today than most untreated LTNPs in the past. In the time between infection and CD4+ decline or AIDS illnesses for an LTNP, sometimes ten years or longer, most untreated HIV-infected people would progress to AIDS and die. Prior to the arrival of combined antiretroviral therapy in 1996, median time from infection to death—even with some forms of treatment available and including LTNPs in the calculations—varied from under eight years to over twelve years in high-income countries, depending on age at infection (14). Today, many young HIV-infected people starting treatment can expect another 40 years of life, and treatment strategies are improving with time (10, 15). The lessons learned from the ongoing research collaborations between LTNPs and scientists may further enhance the effects of anti-HIV treatments.

Note: our references are just a tiny sampling of the work published on this topic. A list of additional references may be found at The Body.

Additional information is also available at:

• Elite controller study led by Dr. Bruce Walker.
• Zephyr Foundation: information resource, advocacy, and networking.

Refrences

1. Baker, B.M., B.L. Block, A.C. Rothchild, and B.D. Walker. 2009. Elite control of HIV infection: implications for vaccine design. Expert Opin Biol Ther 9:55-69.

2. Piacentini, L., M. Biasin, C. Fenizia, and M. Clerici. 2009. Genetic correlates of protection against HIV infection: the ally within. J Intern Med 265:110-124.

3. Goudsmit, J., J.A. Bogaards, S. Jurriaans, H. Schuitemaker, J.M. Lange, R.A. Coutinho, and G.J. Weverling. 2002. Naturally HIV-1 seroconverters with lowest viral load have best prognosis, but in time lose control of viraemia. Aids 16:791-793.

4. Kemal, K.S., T. Beattie, T. Dong, B. Weiser, R. Kaul, C. Kuiken, J. Sutton, D. Lang, H. Yang, Y.C. Peng, R. Collman, S. Philpott, S. Rowland-Jones, and H. Burger. 2008. Transition from long-term nonprogression to HIV-1 disease associated with escape from cellular immune control. J Acquir Immune Defic Syndr 48:119-126.

5. Walker, B.D. 2007. Elite control of HIV Infection: implications for vaccines and treatment. Top HIV Med 15:134-136.

6. O'Connell, K.A., J.R. Bailey, and J.N. Blankson. 2009. Elucidating the elite: mechanisms of control in HIV-1 infection. Trends Pharmacol Sci 30:631-637.

7. Pereyra, F., S. Palmer, T. Miura, B.L. Block, A. Wiegand, A.C. Rothchild, B. Baker, R. Rosenberg, E. Cutrell, M.S. Seaman, J.M. Coffin, and B.D. Walker. 2009. Persistent low-level viremia in HIV-1 elite controllers and relationship to immunologic parameters. J Infect Dis 200:984-990.

8. Sajadi, M.M., N.T. Constantine, D.L. Mann, M. Charurat, E. Dadzan, P. Kadlecik, and R.R. Redfield. 2009. Epidemiologic characteristics and natural history of HIV-1 natural viral suppressors. J Acquir Immune Defic Syndr 50:403-408.

9. Dyer, W.B., J.J. Zaunders, F.F. Yuan, B. Wang, J.C. Learmont, A.F. Geczy, N.K. Saksena, D.A. McPhee, P.R. Gorry, and J.S. Sullivan. 2008. Mechanisms of HIV non-progression; robust and sustained CD4+ T-cell proliferative responses to p24 antigen correlate with control of viraemia and lack of disease progression after long-term transfusion-acquired HIV-1 infection. Retrovirology 5:112.

10. 2008. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 372:293-299.

11. Blankson, J.N. 2009. Effector mechanisms in HIV-1 infected elite controllers: Highly active immune responses? Antiviral Res

12. Pereyra, F., M.M. Addo, D.E. Kaufmann, Y. Liu, T. Miura, A. Rathod, B. Baker, A. Trocha, R. Rosenberg, E. Mackey, P. Ueda, Z. Lu, D. Cohen, T. Wrin, C.J. Petropoulos, E.S. Rosenberg, and B.D. Walker. 2008. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J Infect Dis 197:563-571.

13. Hutter, G., D. Nowak, M. Mossner, S. Ganepola, A. Mussig, K. Allers, T. Schneider, J. Hofmann, C. Kucherer, O. Blau, I.W. Blau, W.K. Hofmann, and E. Thiel. 2009. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med 360:692-698.

14. 2000. Time from HIV-1 seroconversion to AIDS and death before widespread use of highly-active antiretroviral therapy: a collaborative re-analysis. Collaborative Group on AIDS Incubation and HIV Survival including the CASCADE EU Concerted Action. Concerted Action on SeroConversion to AIDS and Death in Europe. Lancet 355:1131-1137.

15. Boyd, M.A. 2009. Improvements in antiretroviral therapy outcomes over calendar time. Curr Opin HIV AIDS 4:194-199.

Return to Debunking denialist myths.