HIV-1 Evolution and Chemokine Receptor Genotypes-Implication for AIDS Progression

25 August, 1998

HIV-1 Evolution and Chemokine Receptor Genotypes-Implication for AIDS Progression

Lymphoid organs are the primary sites fir HIV-1 replication and propagation. In HIV-1 infection, viremia can be detected in all stages and it is now well established that true microbiological latency occurs rarely if at all. To delineate evolutionary patterns of virus replication and distribution in lymphoid tissues during the early phases of HIV-1 infection, lymph node (LN) biopsies were excised from patients after primary infection: Within 3 months, HIV-1 was mostly present in individual virus-expressing cells ( in situ hybridization for HIV RNA) in LNs and plasma viremia was high; In 4-20 months, there was no significant differences in the number of virus-expressing cells in LNs but viremia was low; In long-term >2-3 years, the number of virus-expressing cells was significantly lower as viremia was also low (Pantaleo G et al. 1998: uid=98160246). Thus the level of HIV replication remains elevated during the transition from primary to chronic HIV infection, whereas viremia is significantly downregulated.
Both cellular and humoral immunodeficiency develop in vivo after prolonged infection with HIV. Initial infection with HIV-1 is transmitted by macrophage-tropic/non-syncytia-inducing (M/NSI) viruses and later in infected individuals around the time of transition to AIDS, T cell-tropic/syncytia-inducing (T/SI) viruses emerge that are known to be highly cytopathic in vitro. Glushakova S et al (1998: uid=98160247) found that specific immune responses were enhanced by the productive infection with M/NSI virus isolates, but blocked by T- tropic/SI HIV-1 isolates. The mechanism involves specific irreversible effect on B-cell activity. The hypothesis is that the phenotype switch to T-tropic viruses is a key determinant of acquired humoral immunodeficiency in patients infected with HIV.

It has been found recently that genetic polymorphysms of chemokine receptor genes (CCR5, CCR2, CXCR4) are closely associated with AIDS. These chemokine receptors are coreceptors with CD4 for HIV-1, mutations in which confer protection against HIV-1 infection and/or slow progression of the disease. CCR5 and CXCR4 are used by R5 and X4 viruses, respectively. Most initial infections involve transmission of macrophage-tropic R5 , but T cell-tropic variants can arise later in infection in about 50% of all patients that also use CXCR4 (R5-X4 or X4 viruses). As discussed above in the virus evolution, this is associated with an increased rate of CD4+T cell loss and poor prognosis.

The absence of CCR5 (delta32-CCR5 allele) in ca. 1% of Caucasians very strongly protects against HIV-1 transmission and recent studies showed that a conservative substitution in CCR2 (CCR2-V64I) has a significant impact on a delay in disease progression, but not on HIV-1 transmission (Smith MW et al. 1997: uid=97400624; Kostrikis LG et al. 1998: uid=98160248). In fact, among mutation-carriers, the combined CCR5/CCR2 mutant genotypes were present in 61.5% of long-term non-progressors (LTNP: HIV-1 infection >8 years, CD4+T cells >500/ul, no antiviral therapy) as compared with 29% in progressors (Rizzardi GP et al. 1998: uid=98160216). It is estimated that 25-30% of patients who remain AIDS-free for >16 years attribute their survival to the delta32-CCR5 and V64I-CCR2 mutations. Incidentally and ironically, it is unfortunate that delta32-CCR5 is not present in Africans or Asians who bear the burden of most of the world's HIV infection.

The HIV-1 evolution following primary infection has profound implications for therapeutic strategies. Convincing clinical end results arising from chemokine receptor genotypes of patients would give new venues, based on their modes of action, for drug development that may surpass the benefits of current combination anti-retroviral treatments.

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