A NATURAL RESISTANCE TO HIV INFECTION.

A NATURAL RESISTANCE TO HIV INFECTION.

By Anyikwa Chukwuemeka Louis

INTRODUCTION

It is without doubt that the human immunodeficiency viral disease is the most widespread disease in recent human history. It is a plague, a menace and a nightmare.

A cure has eluded us all for the better part of the time we have known this virus.

HUMAN DEFICIENCY VIRUS

The human immunodeficiency viruses (HIV) are two species of Lentivirus (a subgroup of

retrovirus) that causes HIV infection and over time acquired immunodeficiency syndrome

(AIDS).

HIV infects vital cells in the human immune system, such as helper T cells (specifically CD4+

T cells), macrophages, and dendritic cells. HIV infection leads to low levels of CD4+ T cells

through a number of mechanisms:

1. Pyroptosis of abortively infected T cells

2. Apoptosis of uninfected bystander cells

3. Direct viral killing of infected cells

4. Killing of infected CD4+ T cells by CD8+ cytotoxic lymphocytes that recognize infected cells.

When CD4+ T cell numbers decline below a critical level, cell-mediated immunity is lost, and

the body becomes progressively more susceptible to opportunistic infections, leading to the

development of AIDS.

HIV is a member of the genus Lentivirus,[14] part of the family Retroviridae. Lentiviruses are

transmitted as single-stranded, positive-sense, enveloped RNA viruses. Upon entry into the

target cell, the viral RNA genome is converted (reverse transcribed) into double-stranded DNA

by a virally encoded enzyme, reverse transcriptase, that is transported along with the viral

genome in the virus particle.

The mechanism of the viral Reverse transcriptase is very similar to the role of telomerase in the

lengthening of telomeres.

The HIV virion enters macrophages and CD4+ T cells by the adsorption of glycoproteins on its

surface to receptors on the target cell followed by fusion of the viral envelope with the target

cell membrane and the release of the HIV capsid into the cell.

Entry to the cell begins through interaction of the trimeric envelope complex (gp160 spike)

on the HIV viral envelope and both CD4 and a chemokine co-receptor (generally either CCR5

or CXCR4, but others are known to interact) on the target cell surface. Gp120 binds to integrin

α4β7 activating LFA-1, the central integrin involved in the establishment of virological

synapses, which facilitate efficient cell-to-cell spreading of HIV-1. The gp160 spike contains

binding domains for both CD4 and chemokine receptors.

The first step in fusion involves the high-affinity attachment of the CD4 binding domains of

gp120 to CD4. Once gp120 is bound with the CD4 protein, the envelope complex undergoes a

structural change, exposing the chemokine receptor binding domains of gp120 and allowing

them to interact with the target chemokine receptor. This allows for a more stable two-pronged

attachment, which allows the N-terminal fusion peptide gp41 to penetrate the cell membrane.

Repeat sequences in gp41, HR1, and HR2 then interact, causing the collapse of the extracellular

portion of gp41 into a hairpin shape. This loop structure brings the virus and cell membranes

close together, allowing fusion of the membranes and subsequent entry of the viral capsid.

After HIV has bound to the target cell, the HIV RNA and various enzymes, including reverse

transcriptase, integrase, ribonuclease, and protease, are injected into the cell. During the

microtubule-based transport to the nucleus, the viral single-strand RNA genome is transcribed

into double-strand DNA, which is then integrated into a host chromosome.

HIV can infect dendritic cells (DCs) by this CD4-CCR5 route, but another route using

mannose-specific C-type lectin receptors such as DC-SIGN can also be used. DCs are one of the

first cells encountered by the virus during sexual transmission. They are currently thought to

play an important role by transmitting HIV to T cells when the virus is captured in the mucosa

by DCs. The presence of FEZ-1, which occurs naturally in neurons, is believed to prevent the

infection of cells by HIV.

A RESISTANCE PHENOMENON

A small proportion of humans show partial or apparently complete inborn resistance to HIV, the

virus that causes AIDS.[1] The main mechanism is a mutation of the gene encoding CCR5, which

acts as a co-receptor for HIV. It is estimated that the proportion of people with some form of

resistance to HIV is under 1%.

In an article published in 1996, two teams of scientists reported that people born with changes

in both copies of a gene, called CCR5, seem to have a natural resistance to HIV-1 infection. In

addition, the scientists report that people who have one normal and one altered copy of CCR5

do become HIV-positive, but they tend to progress slowly to full-blown AIDS and often live

longer than most people infected with the virus.

With further analysis, the scientists discovered that those with one copy of the deletion

progressed slowly to full-blown AIDS and lived on average three years longer than those with

normal copies of CCR5.

C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of

white blood cells that is involved in the immune system as it acts as a receptor for chemokines.

This is the process by which T cells are attracted to specific tissue and organ targets. Many

strains of HIV use CCR5 as a co-receptor to enter and infect host cells. A few individuals carry a

mutation known as CCR5-Δ32 in the CCR5 gene, protecting them against these strains of HIV.

In humans, the CCR5 gene that encodes the CCR5 protein is located on the short (p) arm at

position 21 on chromosome 3. A cohort study, from June 1981 to October 2016, looked into the

correlation between the delta 32 deletion and HIV resistance, and found that homozygous

carriers of the delta 32 mutation are resistant to M-tropic strains of HIV-1 infection. Certain

populations have inherited the Delta 32 mutation resulting in the genetic deletion of a portion

of the CCR5 gene.

CONCLUSION

While the delta mutation has been observed to prevent HIV in specific populations, it has shown

little to no effect between healthy individuals and those who are infected with HIV among

Iranian populations. This is attributed to individuals being heterozygous for the mutation, which

prevents the delta mutation from effectively prohibiting HIV from entering immune cells.

Hopefully one day a novel therapy that would utilize the delta mutation on the CCR5 would be

developed.

Hopefully, we would be HIV free someday.

REFERENCE

De Silva E, Stumpf MP (December 2004). "HIV and the CCR5-Delta32 resistance allele". FEMS

Microbiology Letters. 241 (1): 1–12. doi:10.1016/j.femsle.2004.09.040. PMID 15556703.

Heydarifard Z, Tabarraei A, Moradi A (2017). "Polymorphisms in CCR5Δ32 and Risk of

HIV-1 Infection in the Southeast of Caspian Sea, Iran". Disease Markers. 2017ࡉ 4190107. doi:

10.1155/2017/4190107. PMC 5676439. PMID 29209099.

Ruiz-Mateos E, Tarancon-Diez L, Alvarez-Rios AI, Dominguez-Molina B, Genebat M, Pulido I,

Abad MA, Muñoz-Fernandez MA, Leal M (2018). "Association of heterozygous CCR5Δ32 deletion

with survival in HIV-infection: A cohort study". Antiviral Research. 150ࡉ 15–19. doi:10.1016/

j.antiviral.2017.12.002. PMID 29221798.

Chan DC, Kim PS (1998). "HIV entry and its inhibition". Cell. 93 (5): 681–4. doi:10.1016/

S0092-8674(00)81430-0. PMID 9630213.

Wyatt R, Sodroski J (1998). "The HIV-1 envelope glycoproteins: fusogens, antigens, and

immunogens". Science. 280 (5371): 1884–8. Bibcode:1998Sci...280.1884W. doi:10.1126/science.

280.5371.1884. PMID 9632381.

International Committee on Taxonomy of Viruses (2002). "61.0.6. Lentivirus". National Institutes

of Health.

Pope M, Haase AT (2003). "Transmission, acute HIV-1 infection and the quest for strategies to

prevent infection". Nature Medicine. 9 (7): 847–52. doi:10.1038/nm0703-847. PMID 12835704

Scutti S (2014). "Why Some People Are Naturally Immune To HIV". Medical Daily. Retrieved

2015-01-20.