Volume 6, No 3 - 1998
Natural Resistance to HIV/AIDS
Up until a few years ago, HIV-1 infection was regarded as an inevitably progress-ive and inexorably fatal disease. In recent years advances in HIV/AIDS research have been able to somewhat modify this sombre and fatalistic outlook on HIV infection. Firstly, the advent of powerful and effective anti-retroviral drugs, and specifically the use of synergistic combinations of drugs, have significantly increased the potency of the antiviral attack and effectively forestalled the development of drug resistance (previously an inevitable consequence of mono-therapy). Modern antiretroviral drug strategies have now been able to convert HIV-1 from being an inevitably lethal infection to a chronic medical condition which is controllable by long term therapy.
The second important breakthrough has been the recent discovery that there are certain individuals who possess natural mechanisms to resist HIV infection, or, if they do become infected, are able to control the infection so effectively that they remain asymptomatic for long periods of time. Although these cases are still comparatively rare, studies of them have provided very important insights into natural mechanisms for resistance, or for overcoming HIV infection, which could be exploited for developing new antiretroviral drugs or HIV vaccines.
Natural resistance to HIV/AIDS can be considered at two levels:-
A) Resistance to becoming infected with the virus: There are individuals who are repeatedly exposed to HIV infection but remain seronegative. They are also referred to as highly exposed seronegative individuals. They include persons who continue to indulge in high risk activities such as numerous unprotected sexual contacts with multiple partners yet still remain antibody negative.
B) Persons who are infected but who resist progression to AIDS: They are referred to as long-term non-progressors (LTNP). These HIV-positive individuals have not been on antiviral therapy yet have remained clinically well and have reasonable immune function with high and stable CD4+ lymphocyte counts for many years without showing signs of immune compromise or evidence of progression to AIDS.
A. RESISTANCE TO HIV INFECTION
Transmission of HIV is very inefficient in comparison to other human viruses. It is therefore difficult to establish how often exposures to HIV in nature which fail to establish infection are due to resistance or are merely part of the intrinsic inefficiency of HIV trans-mission. There are, however, a number of examples of defined instances of HIV exposure which provide opportuni-ties for the study of resistance to HIV infection:-
Two kinds of resistance to HIV infection have been described - that due to mutations in co-receptors used by HIV to establish infection; or, if HIV infection does become established, there are some individuals who appear to be able to mount a particularly vigorous and effective immune response which is able to overcome and clear the infection.
a) Mutation in HIV co-receptor: The role of the chemokine receptors which may serve as co-receptors for HIV, has recently been established. Not surprisingly, therefore, individuals with mutations in the alleles coding for this receptor have been demonstrated to be resistant to HIV infection.
Chemokines are chemical mess-engers which transmit activation signals to recipient cells. For example, the CC chemokines called RANTES, MIP-1a and MIP-1b convey chemotaxis signals to leukocytes which cause them to move towards areas of inflam-mation. Early last year it was shown that these chemokines are also able to effectively inhibit HIV infection of cells. The receptor for the CC chemokines is called CCR-5 and this has been demonstrated to be a crucial co-receptor for macrophage tropic (M-tropic) strains of HIV-1. The M-tropic strains of HIV-1 are the main strains which are responsible for establishing infection and they predominate in the early stages of infection. These strains target macrophages and CD4+ lympho-cytes. (T-tropic strains predominate in the latter stages of infection and infect CD4+ lymphocytes but not macrophages, and utilize another co-receptor called fusin). The CCR-5 receptor is responsible for the penetration and entry of HIV-1 into the cell after the virus has attached to the CD4 cell surface antigen by its envelope glycoprotein gp120. Mutations in the CCR-5 receptor could therefore be expected to result in cells becoming resistant to HIV-1. A small number of individuals who are homozygous for the allele of CCR-5 have been found amongst the highly exposed group of sero-negative individuals mentioned above. Lymphocytes from these individuals have been shown to be highly resistant to infection with HIV-1. As yet no individuals with the homozygous mutant have been found to be HIV infected. Approxi-mately 1% of the Caucasian population are homozygous and 15 to 20% are heterozygous. To date, mutations in CCR-5 have not been found in African subjects. Hetero-zygosity is thought to provide partial protection, i.e. individuals with one mutant copy of the CCR-5 gene appear to progress more slowly to AIDS than individuals without this mutation. Mutations in the CCR-5 chemokine receptor have thus been shown to be a mechanism of HIV resistance in a small number of persons. Many highly exposed sero-negative individuals, however, do not have a CCR-5 mutation and the explanation for their resistance still needs to be elucidated.
b) Immune protection against HIV infection:
i) Infants: Only about 25% of infants born to HIV infected mothers are persistently infected with HIV and progress to AIDS. Of the remaining 75%, many are uninfected because an in-adequate dose of virus crosses the placenta. However, investi-gations of foetuses from HIV positive mothers who were electively aborted in early pregnancy have shown that the majority have HIV DNA sequences in cells from various organs. From these studies it would therefore appear that the majority of infected foetuses are able to overcome and clear the infection. The mechanism, however, is still unclear as the immune system of the foetus is immature and ineffective in clearing most transplacentally transmitted viruses.
Further evidence of immune protection in the infant is the manifestations of lymphocyte reactivity to HIV which are found in seronegative infants. In one study, some 40% of uninfected infants demonstrated lympho-cyte reactivity (by IL-2 production) in their cord blood and peripheral blood lympho-cytes in response to several HIV peptides including gp160 and nef proteins. Even more convincing is the finding of HIV-specific cytotoxic T-lymphocytes imply-ing continuous antigenic stimula-tion and therefore viral replication in the host.
The most striking and widely publicized illustration of the ability of an infant to overcome HIV infection is that of a child in Los Angeles born to an HIV positive mother, who had negative HIV cultures of blood at birth, but then produced sub-sequent positive cultures at 19 days and 51 days. However, numerous follow-up blood cultures were negative and the child has remained seronegative and clinically well for at least 5 years afterwards. Several other cases of seroreverting infants have also been described.
ii) Adults: Seronegative adults who have been exposed to HIV also have demonstrated an immune response to the virus as shown by lymphocyte reactivity in response to HIV antigens. These individuals include those having unprotected sexual inter-course with multiple HIV infected partners, intravenous drug abusers, prostitutes, recipients of blood or blood products contaminated with HIV and healthcare workers who have been exposed to HIV through needlestick injuries with HIV infected blood. Some of the possible mechanisms could include exposure to virus-free antigens of HIV or defective strains of HIV. However, the finding of CD8+ cytotoxic T-lymphocytes which were MHC class I restricted, would indicate at least one round of viral replication and suggest that the immune system was able to overcome and clear the infection without the production of antibodies.
B. LONG-TERM NON-PROGRESSORS
There is a wide range of clinical responses to HIV infection in humans. In about 80% of HIV infected individuals AIDS develops within the median time of 10 years. Individuals with this clinical course are referred to as typical progressors. In 10% of HIV infected subjects AIDS develops within 2 to 3 years after infection; these individuals are referred to as rapid progressors. On the other side of the spectrum, about 5 to 10% of HIV infected persons remain asymptomatic for at least 7 to 10 years and often up to 20 years after HIV infection, despite being on no anti-retroviral therapy. Their immune function is relatively well maintained with CD4+ lymphocyte counts above 600/mm3 and low plasma levels of HIV-1 RNA. Biopsies of their lymph nodes confirm the non-progressive nature of their infection with little evidence of the hyperplastic and involuted changes or lymphocyte depletion seen in lymph node tissue from subjects with progressive disease. These individuals are referred to as long-term non-progressors (LTNP), or long-term survivors. Both viral as well as host factors play a role in long-term non-progression of HIV.
1. Viral factors: Culture of HIV from the blood of LTNPs is difficult and often unsuccessful because of the lower plasma viral load. Molecular characterization of these isolates have revealed the presence of a number of genetic defects which could be the basis for the attenuation of the virus. Occasion-ally genetic defects such as in the NfkB or Sp1 site within the long terminal repeats of the virus have been demonstrated. However, the best documented and studied genetic lesions associated with virus attenuation in LTNPs are the nef deletion mutants. The nef gene is a crucial regulatory gene of HIV-1. Monkeys experimentally inoculated with simian immuno-deficiency virus (SIV) which have deletions in their nef gene, show no signs of disease and have low viral loads in the plasma and normal CD4+ lymphocyte counts. In humans, nef deleted mutants of HIV-1 have also been shown to play a role in the genesis of long-term non-progression. The most con-vincing demonstration came from a study published by Australian workers at the end of 1995. An HIV infected male homosexual donated blood and infected some 7 recipients over a period of 3 years (in the era before blood was routinely tested for HIV). Surprisingly, neither the donor nor any of the recipients developed any symptoms and had remained healthy (with the exception of 2 who died from unrelated causes). Molecular studies on isolates from 4 of the 8 subjects demonstrated defects in the nef gene. Although nef deletion mutants still only account for a very small number of LTNPs, they have aroused great scientific interest because of their potential usefulness in the develop-ment of an HIV vaccine.
2. Host factors: From studies of a number of cohorts of LTNPs, a pattern appears to be emerging characterizing these individuals as having immune responses which are quantitatively and qualitatively more potent and more effective in controlling HIV infection. Vigorous virus-specific humoral and cell mediated immune responses have been demonstrated in these subjects. High titres of potent neutralizing antibodies to a wide spectrum of HIV isolates have been shown to be present in the sera of LTNPs. In addition, there are strong CD8+ cytotoxic lymphocyte responses in these individuals, reflecting long-standing stimulation of the immune system by continuing viral replication. The resulting immune response is able to effectively suppress viral replication and thus relatively low viral loads are found in their plasma and high CD4+ lymphocyte counts are maintained in the blood. The lymph node architecture remains intact and the degree of virus trapping in the follicular dendritic network in the lymph nodes is considerably lower.
Precisely why some individuals respond with a more favourable immune response than others is still not clear. It is also uncertain whether the more effective immune response is a cause of lower viral loads or whether the more effective immune response is the con-sequence of infection with more attenuated viral variants.
Long-term non-progression as well as resistance to viral infections is apparently a relatively uncommon phenomenon. However, the importance of the phenomenon of resistance to viral infection lies in the lessons that it teaches which could be used in developing therapeutic and vaccine interventions to control and prevent infection. For the present, and for the majority of HIV infected individuals, antiretroviral therapy remains the only effective way of controlling HIV infection.
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