07 Sep 2023

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A genetic variant found by an international team of scientists present only in people of African ancestry seems to halve the set point viral load in people with HIV who are not on treatment. The set point is where viral load stabilises after the early stage of infection, and it determines how fast HIV damages the immune system. This variant may be protective against quick disease progression and lessen transmission, concludes the paper published in the journal Nature.
Several genetic factors have been identified that can affect the course of the infection. However, most studies on genetic determinants have focused mainly on people of European ancestry. Among the genes involved, variants of Human Leucocyte Antigen, or HLA, (proteins responsible for immune system regulation) and CCR5 genes have been found to have the most pronounced effect on viral load levels after acute infection.
Given the large genetic diversity present in people of African ancestry and the HIV burden in Africa, the researchers looked for genetic variants in people of African ancestry that can affect viral load.
The viral load that the body settles at within a few weeks to months after infection with HIV. Immediately after infection, a person’s viral load is typically very high. After a few weeks to months, this rapid replication of HIV declines and the person’s viral load drops to its set point. A higher viral set point suggests that, in the absence of treatment, disease will progress faster than in a person with a lower set point. 
A unit of heredity, that determines a specific feature of the shape of a living organism. This genetic element is a sequence of DNA (or RNA, for viruses), located in a very specific place (locus) of a chromosome.

The body’s mechanisms for fighting infections and eradicating dysfunctional cells.

The primary white blood cells of the immune system, which signal to other immune system cells how and when to fight infections. HIV preferentially infects and destroys CD4 cells, which are also known as CD4+ T cells or T helper cells.
The process of viral multiplication or reproduction. Viruses cannot replicate without the machinery and metabolism of cells (human cells, in the case of HIV), which is why viruses infect cells.

While several variants were described with minor effects on set point viral load, a particular variant found in 4 to 13% of people of African ancestry had a measurable effect that could significantly reduce viral replication.
Without treatment, HIV infection follows a course divided into three phases. The initial phase is called ‘acute infection’ and involves the entry of the virus into the body, a ‘silent period’ and a burst of viral replication that produces millions of virus copies. This phase spans the first two to three months of the infection while the immune system is still unprepared. Once the immune system develops the necessary tools to limit the virus, the viral load starts to drop and the destruction of CD4 cells is slowed. This phase is called ‘chronic infection’ and can last from several years to over a decade before the loss of CD4 cells leads to the third final phase known as AIDS. The chronic infection phase becomes established when the immune responses and the virus reach an equilibrium. The amount of virus observed at the beginning of this phase is called set point viral load.  The level of the viral load set point influences the speed at which CD4 cells are lost and the progression of HIV disease.
Genetic diversity is essential for the survival of a population. While we all have the same genes, there are small differences in the sequences of these genes that can lead to slightly different overall individual features when they are expressed. These different forms of our genes are called genetic variants. These variations can also influence responses to infectious agents.
An example of a genetic variant that has a profound effect on HIV is the one observed in the gene that encodes the CCR5 receptor. This receptor is expressed on the surface of certain immune cells like the CD4 cells. HIV requires the receptor to enter the cell and replicate inside; the delta variant however makes the receptor dysfunctional and unrecognisable by the virus, so it cannot enter and destroy the immune cells. 
The investigators looked at genetic determinants that could lower set point viral load in 3 879 participants living with HIV of African ancestries. The majority of the participants were African Americans (2 535 people) with a minority of Kenyans (147 people). Later, to confirm their observations, they included genomic data from 1 197 people living in east and southern Africa and people of African descent living in Switzerland.
Alongside known genetic variants, a new location on chromosome 1 (the first chromosome pair out of 23 in humans) was found to be associated with a lower set point viral load. In the location associated with reduction in the set point viral load, 16 gene variants were discovered with varying reducing effects on viral load. The location of association was found to include four different gene sequences, among which was the CHD1L gene. More particularly, in a non-coding region situated ‘behind’ these was the top variant sequence (A) that halved the set point viral load. Between the top variant (A) and the CHD1L gene, a new associated variant was discovered that had a similar effect on the set point viral load.  
Following these findings, the investigators looked at the association of these variants on the nearby four genes. Among the analysed genes, the presence of CHD1L was strongly associated with the variant sequences. CHD1L is a gene that encodes a helicase (a molecule involved in the repair of DNA damage). That would make sense, as one way of eradicating viruses from a cell is ‘cutting’ them out with the help of these error-correcting molecules. Furthermore, CHDL1 interacts with another molecule called PARP-1 involved in the integration of the HIV genome into the human genome and the activation of HIV’s principal regulatory protein, called Tat.
Given these findings, the researchers concluded that CHDL1 is most likely to account for the reduction in set point viral load while the variant sequences may increase its expression or improve its function.
To test and confirm this gene’s association with HIV control, they next tested their hypothesis by either silencing the gene or removing it altogether in different cell types.
CHDL1 knockdown (silenced) and knockout (removed) cell lines mostly showed increased rates of HIV infection and replication. Next, they tested this on macrophages, which are immune cells that play a major role in disseminating HIV throughout the body during the earliest stages of infection. Macrophages also provide a hiding place where HIV cannot be easily detected or eliminated by immune system cells. The researchers found that CHDL1 in macrophages reduces the replication of the virus.
To better illustrate the significance of the effect of the top variant (the one with the greatest reducing effect on viral set point) found in this study, we can compare it to the known genetic variant called CCR5delta32. The latter, if present as a single copy inherited from only one of the parents leads to a significant reduction in set point viral load comparable to the one achieved by the top variant described in this study. When two copies of the CCR5delta32 gene are inherited, one copy from each parent, then the person becomes resistant to HIV infection.
The differences in viral load associated with the genetic variants identified by these studies are likely to have modest effects on disease progression and the likelihood of transmission in most people.
Understanding more about the genetic factors that influence HIV’s ability to disseminate in the body soon after infection and persist in the body may help in the development of new treatment and prevention options, the researchers conclude.
McLaren PJ. et al. Africa-specific human genetic variation near CHD1L associates with HIV-1 load. Nature, published online, 2 August 2023.
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