HIV Protection

Nov 18, 2006Updated 3 weeks ago

HIV belongs to a family of viruses known as retroviruses (Retroviridae). Retroviruses contain an inner portion or core that consists of two identical strands of RNA and three enzymes not found in human cells that are essential for the virus to replicate. Each strand of RNA has a molecule of reverse transcriptase attached to it. Two other enzymes necessary for viral replication are also included in the viral core - protease and integrase. The core is enclosed in a protein coat known as the capsid, which is further covered or enveloped in a double layer of lipid molecules acquired from the cell membrane of the infected host cell.

Replication of HIV and other retroviruses involves a series of steps or processes:

  • Binding: attachment to the host cell
  • Fusion: viral envelope becomes “one” with the host cell membrane so that the contents of the viral core can enter the host cell cytoplasm
  • Reverse transcription: production of a DNA copy of viral RNA. Human genes are composed of DNA, which is transcribed into RNA and then translated into protein; whereas, the retroviral genes are composed of RNA, which is then transcribed into DNA (opposite direction of human genes = reverse transcription)
  • Integration: incorporation of the viral RNA strand and the newly synthesized DNA strand (hybrid molecule) into the host cell DNA
  • Provirus synthesis: host cell recognizes DNA/RNA hybrid, and produces (synthesizes) a DNA strand to replace the RNA strand resulting in a double-stranded DNA copy of the original viral RNA or provirus
  • Integration: incorporation of the DNA provirus into the nuclear DNA that makes up the chromosomes of the host cell
  • Viral transcription: transcription of messenger RNA (mRNA) by the integrated provirus
  • Viral protein synthesis: production of new viral proteins by mRNA that was transcribed by the integrated provirus
  • Protein cleavage: process whereby the protease enzyme contained in the viral core cuts proteins synthesized by mRNA into functional units
  • Viral assembly: assembly of cleaved proteins into new viral particles capable of infecting new cells
  • Budding: process during which the newly assembled viral particle is released through the host cell membrane
In order to infect host cells, HIV must first bind to a receptor on the cell surface - a CD4 antigen found on helper T-cells, monocyte/macrophages and some other types of body cells (dendritic cells and glial cells). The depletion of normally functioning CD4 cells eventually leads to immune deficiency. In addition to CD4, a co-receptor is also necessary for HIV entry into the host cell – this co-receptor, CCR5, is one of a group of chemical messengers known as chemokines. A protein, glycoprotein 120, on the surface of the HIV particle binds specifically to CD4 and the co-receptor forming a complex that functions as a key allowing the viral envelope to join with the host cell membrane and the virus to enter the host cell.

An allele mutation has been identified that provides resistance against HIV-1 by blocking attachment to the chemokine receptor so that the virus cannot gain entry. The mutation consists of a 32 nucleic acid deletion that prevents expression of the receptor on the cell surface. In the homozygous state, the mutation provides almost complete resistance, and in the heterozygous state partial resistance is provided with slower disease progress.

The CCR5-Delta32 deletion mutation has been found with a high frequency in European populations, but has not been found in African, Asian, Middle Eastern and American Indian populations. The frequency of the resistance allele is estimated at approximately 10% in European populations. Scientific controversy exists over the reason(s) for the origin of the mutation and the high frequency in European populations. The absence of the resistance allele in populations outside Europe suggests that it has a recent origin.

Selective pressure arising from the Black Death and Great Plague pandemics in Europe (bubonic plague) has been suggested as a reason for the mutation and its high frequency in the European population, with the CCR5 mutation providing protection against Yersinia pestis, the bacterium responsible for plague. Although this hypothesis is gaining widespread acceptance, the smallpox virus (Variola major) has also been suggested as a likely candidate for providing the selective pressure that resulted in the CCR5 mutation. Galvani and Slatkin suggest that ongoing smallpox epidemics in the last 700 years in Europe represent a weaker, but more continuous selection for the CCR5 mutation that provides protection against HIV infection as well as smallpox. Galvani and Slatkin support their hypothesis by pointing out that HIV and pox viruses both infect leukocytes resulting in dysfunction of cellular immunity, and gain entry to leukocytes by using chemokine receptors; whereas, the clinical characteristics of HIV and Yersinia pestis are quite distinct.

Despite the disagreement concerning the origin of the mutation that confers protection against HIV infection, there is general agreement that the discovery has promise in the treatment of HIV. By interfering with the expression of the chemokine receptor necessary for HIV-1 cell attachment, scientists may be able to prevent the virus from invading new cells in those already infected.


Galvani AP, M Slatkin. Evaluating plague and smallpox as historical selective pressures for the CCR5-delta 32 HIV-resistance allele. Proc Natl Acad Sci USA. 2003;100(25):15276-15279.

Galvani AP, J Novembre. The evolutionary history of the CCR5-Delta32 HIV-resistance mutation. Microbes Infect. 2005;7(2):302-9.

Sabeti PC, E Walsh, SF Schaffner, P Varilly, B Fry, HB Hutcheson, M Cullen, TS Mikkelsen, J Roy, N Patterson, R Cooper, D Reich, D Altshuler, S O'Brien, ES Lander. PLoS Biol. 2005;3(11):e378.

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