Natural history of elite controllers

26 June 2017. Related: Basic science and immunology.

Gareth Hardy, HIV i-Base

A small subset of HIV positive people, referred to as elite controllers, are able to spontaneously control HIV infection to below 50 copies/mL without ART.

Although genetic studies have identified HLA-type as a likely contributor to spontaneous control of viraemia (SCV), at least a third of cases do not carry these alleles. [1]

In a recently published study in AIDS, Otto Yang and colleagues at the University of California, Los Angeles, presented a review from almost 30,000 HIV positive people attending AIDS Healthcare Foundation clinics in LA and Miami to assess the frequency, demographics and outcome of SCV. [2].

To be included in the study, participants had to have at least three viral load measurements within a one-year period. SCV was defined as having at least three consecutive viral load measurements <50 copies/mL plasma over one year, in the absence of ART. Loss of SCV was defined as having three consecutive viral load measurements >50 copies/mL plasma or a single measurement >1000 copies/mL of plasma. Transient viral load measurements >50 copies/mL plasma that did not lead to loss of SCV were defined as viral blips. Follow up was cut off after loss of SCV or initiation of ART, which in itself was not considered loss of SCV. Comparisons were made between those with SCV and those without, and between those who maintained SCV and those who became viraemic.

Out of 29,811 records, 53 HIV positive people met the definition of SCV (0.18%). Twenty six (49%) were women and three were (6%) were transgender (male to female), 33 (62%) were black, 17 (32%) were white (four were latino), and one (2%) was Asian. Data on route of transmission was collected from 26 people, of which 24 (45%) were sexual and two (4%) were via I.V. drug use. The HLA allele B*5701 which is protective against HIV disease progression was only present in two people, who were both white, out of 18 who were screened. Over the observation period, nine people became viraemic after a mean of 6.1 years (SD 3.5, range: 1.5 to 11.3). Five people started ART without becoming viraemic.

SCV was significantly more likely to occur in women than men, (26/4517 [0.58%] women versus 24/24,603 [0.1%] men, p <0.001). SCV was also significantly more likely to occur in blacks than whites, (33/10,089 [0.33%] blacks versus 17/16,559 [0.1%] whites, p <0.001). The highest frequency of SCV was among black women (20/2841 [0.7%]) and the lowest amongst white men (11/15,064 [0.07%]).

In the nine people who lost SCV during the study period, the rate of loss was linear over the estimated duration of infection, corresponding to 1.22% per year, which equates to a half-life of 40.8 years. There were no significant differences in rate of SCV loss according to race, sex or estimated age at time of infection.

Viral blips occurred in 18 people and were significantly associated with progression compared to those without blips (p = 0.04). The frequency of viral blips was higher for the nine people who lost SCV (15.9% [10/63] viral load measurements) compared with the 44 people who maintained SCV (5.8% [28/484]), but were no greater in magnitude or any more frequent before loss of SCV.

This research represents the most detailed assessment of SCV frequency according to sex and race so far and finds that sex and race are significant determinants of SCV prevalence, with higher rates in women and black people. In addition, more frequent viral blips were associated with loss of SCV.

The researchers also performed a mathematical assessment of viral blip magnitude in sustained and non-sustained SCV groups and concluded that blip magnitudes are consistent with low-level viral set points (at <50 copies/mL) and reflect variation around stable means.

In the discussion section of this paper the authors concluded, perhaps controversially, that “persons with SCV are not qualitatively different, but rather represent an extreme in the continuum of log-normally distributed plasma viraemia set points across persons with untreated infection”, rather than being qualitatively distinct from other persons with HIV.

Comment

A huge variety of biological factors, some known and some not known, influence and determine the continuum of viraemia containment. SCV is therefore liable to have underlying complex biological factors that determine it.

References

1. Pereya F et al. Genetic and immunologic heterogeneity among persons who control HIV infection in the absence of therapy. J. Infect Dis. 2009:(197);563-571.
   https://academic.oup.com/jid/article-lookup/doi/10.1086/526786
2. Otto OY et al. Demographics and natural history of HIV-1-infected spontaneous controllers of viremia. AIDS 2017(31);1169-1180.
   http://journals.lww.com/aidsonline/Abstract/2017/05150/Demographics_and_natural_history_of_HIV_1_infected.5.aspx