*5.3.3. Viral fitness*

**5. Elite controllers**

individuals in some parts of Africa.

HIV negative (seronegative).

**5.2. Global prevalence**

**5.1. Serodiscordant infection: Definition**

188 Trends in Basic and Therapeutic Options in HIV Infection - Towards a Functional Cure

**5.3. Classification of HIV natural resistance**

*5.3.1. Highly Exposed Persistently Seronegatives (HEPSs)*

but persistently remain seronegative (do not develop antibody to HIV).

*long-term nonprogressors (LTNPs)*

*5.3.2. Long-Term Nonprogressors (LTNPs)*

Elite controllers are referred to as individuals having the ability to spontaneously suppress viral load and maintain HIV control mainly achieved soon after seroconversion. These individuals may not be common in the population, about <1 %, and may best be understood using serodiscordant HIV infection. There is evidence of an increasing number of these

HIV natural resistance can best be described using serodiscordant HIV infection in sexual partners. Serodiscordant HIV infection recognises couples/sexual partners in which one may be either HIV seroconcordant-seropositive or seroconcordant-seronegative or the partners are having different serostatuses [46]. Serodiscordant HIV infection refers, therefore, to partners adequately exposed to HIV infection in which one is HIV positive (seropositive) and the other

The prevalence of HIV serodiscordant infection in seronegative population has not been well documented. About 0.5 % (one in 200) people are reported in America [47]. Scott-Algara et al. [48] in 2003 reported that between 5 and 15 % of individuals of different populations at risk of HIV infection (regular partners of seropositive subjects, prostitutes and intravenous drug addicts) show no signs of apparent infection by HIV in spite of many years of exposure. However, some studies have indicated an estimate of about 5 % in Africa. Fowke et al. [49] in a cohort study showed that 4.3 % of HIV-1-exposed seronegative prostitutes in Kenya were persistently HIV negative after 12 years of follow-up study. Other reports have shown an increasing number of persistent serodiscordant-seronegatives and the risk of HIV transmission

within stable serodiscordant partners across 23 countries of sub-Saharan Africa [50].

Those individuals who are serodiscordant-seronegative may possess natural resistance to HIV infection. They can be grouped into two: *highly exposed persistently seronegatives (HEPSs) and*

They are individuals who are repeatedly exposed to HIV through different routes of exposure

About 5–10 % of HIV-infected people remain asymptomatic for about 7–20 years after infection despite being on no antiretroviral therapy. Their immune function is well controlled with CD4+ The phenomenon of viral 'fitness' relates to the pathogenicity of certain strains of HIV. HIV replicative capacity (RC) is attributed as a component of viral fitness [55]. RC, therefore, is a measure of the ability of the virus to replicate successfully in a given environment [56] which tends to affect controllers of HIV. In LTNP, a number of genetic defects have been associated with the virus. Such documented defects or genetic lesions include the NF-κB or SP1 site and the nef mutant gene within the long terminal repeats of the virus [57]. According to Learmont et al., some LTNPs have shown to possess this mutant gene (nef) [58]. Also faster rates of disease progression have been observed in Ugandan individuals infected with subtype D compared with subtype A isolates. The current concept is based on the viral load dynamic equilibrium set point that is established between the production of virus (VR) (dependent on the number of activated CD4 cells) and the suppression of replication and elimination of virusproducing CD4 cells by adaptive immunity [51, 52]. Here, the elite controllers fall into extreme low viral load carriers that are undetectable, though other researchers still maintain effective immune clearance of EC as the major factor [58]. From studies, vigorous virus-specific humoral and cell-mediated immune responses have been detected. For example, high titres of potent neutralising antibodies have been found in sera of LTNPs with strong CD8+ cytotoxic Tlymphocyte cells [59]. Genetic differences in human leukocyte antigen (HLA) alleles have also been shown to influence HIV disease susceptibility [60] and disease progression [61]. In particular, HLA B\*5701 has been found as reported by Migueles et al. to be highly overrepre‐ sented in LTNP. Other immunological factors found include natural killer (Nk) cells in resistant Vietnam population [48] and high levels of IL-2 (interleukin-2) found in resistant infants born to HIV-positive mothers.

A mutant allele of CCR5 with a 32-base pair deletion (CCR5-delta-32) discovered in 1996 confers resistance to the highly exposed group of seronegative individuals [62,63]. It is often seen in populations of European origin (in Caucasians, 1 % are homozygous, while 15–20 % are heterozygous), which encodes a nonfunctional truncated protein. Homozygotes for the Δ-32 allele are believed to exhibit a strong and complete resistance to HIV infection, whereas heterozygotes delayed progression to AIDS as observed in LTNP [64]. This mutation is hypothesised to be absent in African origins and certain Asian populations.
