Christina Psomas, MD, PhD Interview
Christina Psomas is Specialist in Infectious Diseases, clinician and researcher, at the University Hospital in Montpellier, France.
She is well recognized for her work on HIV persistence and HIV inflammation with a series of international papers on these topics.
She agreed to answer a couple of questions.
Alain Lafeuillade: Now that HIV is a "chronic" disease in most patients due to daily antiretroviral therapy, what are the main challenges that remain ahead?
Christina Psomas: Indeed, about 90% of treated persons living with HIV have an undetectable plasma viral load (less than 50 HIV copies/mL). Yet, 6 to 24% of these virologic responders do not restore their CD4 count as they should, exposing them to the risk of immune deficiency-linked morbidities. The main reason for that is the persistence of a state of hyperactivity of the immune system in these patients.
Thus, the first scientific challenge on an individual level is to find a way to prevent these long-term complications and to fight against persistent immune activation. Another major issue on an individual and populational scale is reaching the goal of truly controlling and ultimately ending the HIV and AIDS pandemic. New infections still persist each year and the magnitude of this phenomenon directly depends on the cascade of care in each country: too few people with HIV are aware of their infection, and many HIV-infected populations do not receive efficient antiretroviral treatment. Given the availability of highly effective therapeutic regimens for HIV infection, the second challenge is efficiently identifying a maximum number of HIV-infected persons through voluntary HIV testing and initiating antiretroviral therapy (ART), which is a major operational and economic challenge.
This residual immune activation also fuels the so-called non AIDS-linked morbidities that currently are the major cause of morbi-mortality in treated HIV-infected subjects.
Prevention approaches tailored to each population, generalized HIV testing, as well as retention to care should eliminate undiagnosed or untreated infections that fuel the HIV epidemic.
Finally, two scientific challenges still remain: the development of an HIV vaccine for HIV uninfected people that is imperative if a truly substantial reduction in epidemic transmission is to be achieved, and the development of approaches to cure the latent reservoirs of HIV infected people on ART, which would alleviate the need for lifelong treatment.
AL: What is the status of persistent inflammation in HIV-treated patients, its causes, and consequences?
CP: A hallmark of HIV infection is a state of global immune activation that is only partially restored under ART. Apart from immune deficiency and impaired immune restoration, this chronic immune activation may result via various mechanisms in non-AIDS linked morbidities such as atherothrombosis, liver steatosis, metabolic syndrome, osteoporosis, neurocognitive disorders, kidney failure, frailty, and some types of cancer.
Various causes may combine to provoke this immune hyperactivity. A first cause is the presence of the virus itself, via residual HIV replication under ART, or even just viral production from HIV reservoirs without active cycles of infection. A second cause is microbial translocation induced by deterioration of the gut barrier (GALT) happening already during acute infection, which is irreversible and paves the way to continuous passage of intestinal microbes in the human organism. A third cause is presence of simultaneous coinfections such as hepatitis B and C, and herpes viruses (mainly cytomegalovirus). A fourth set of causes is linked to some effects of HIV on the immune system itself: CD4+ T lymphopenia, immunosenescence and imbalance in the CD4+ T cell subpopulations (Th17 and T regulatory cells). Some studies try to elucidate physiopathogenic links between persistent immune activation and comorbidities, which would enable to tailor prevention, early diagnosis, as well as therapeutic approaches of non-AIDS-linked morbidities to each patient.
AL: Does chronic inlammation concern all patients with undetectable viremia? If not, why and how does it work?
CP: Chronic inflammation and immune activation have been known to be independent predictors of disease progression.
Even in the absence of detectable plasma viral load when individuals are treated with ART, immune activation is not normalized compared to healthy subjects.
Only a small fraction of HIV-infected individuals (1-2%) are long-term non-progressors (LTNPs) characterized by low plasma viral loads, relatively stable CD4+ T-cell counts and no AIDS-related symptoms over years without ART. These HIV controllers tend to show reduced immune activation compared to HIV non-controllers. Moreover, within this group of LTNPs, undetectable HIV long-term non-progressors (Elite Controllers) compared to viremic LTNPs seem to present a more favorable immunological profile with lower markers of immune activation, which might be associated with more stable CD4+ T-cell counts over time and thus, less disease progression.
How some individuals are able to more effectively control immune activation than others is a key question. Studies involving nonhuman primate showed that the most striking feature of simian immunodeficiency virus infection in natural hosts is the absence of aberrant chronic immune activation. This is probably related to the fact that even if the causes of persistent immune activation are unclear, they likely result from multiple factors, including residual HIV replication within the reservoirs, presence of coinfections, dysbiosis, damage to the lymphoid tissues, age and loss of T regulatory cells.
Despite extensive study of pathways of immune activation, multiple studies attempting to lower persistent immune activation have not yet succeeded to alter clinical outcome. The best strategy to date to decrease immune activation and inflammation in HIV is early initiation of ART.
AL: Regarding acute HIV infection, does cART initiated at this stage of disease influences the immunological outcome and in which way?
CP: During acute HIV infection the virus disseminates from the initial site of infection into various tissues and organs. Even if this period approximately covers 4-5 weeks, the virus quickly establishes a proviral reservoir within days of acquisition. Only a few studies to date have evaluated the timing of immune activation in humans. One such study in South African women detected CD8+ T cell activation within 1-3 days following detectable viral load. Even if immune activation appears to confer initial benefits in controlling viremia via an HIV-specific memory CD8+ T-cell response, persistence of this immune activation is associated with long-term deleterious effects, as well as immune dysfunction. Early in HIV acquisition, CD4+ Th17 cells are depleted from the gut-associated lymhoid tissue, leading to structural and functional changes in the mucosa, which is highly correlated with systemic immune activation and disease progression. Recent studies have shown that initiation of ART in early acute infection before peak viremia (Fiebig I/II) qualitatively and quantitatively prevents the loss of Th17 cells and reverses mucosal and systemic immune activation. Later antiretroviral treatment (Fiebig III) only partially restores numbers and polyfunctionnality of CD4 T cells, and does not normalize CD8+ T cell activation. Other studies suggested that ART initiated during acute infection obviously protects central memory CD4+ T cells, while reducing the size of HIV reservoirs and viral diversity. Size of HIV reservoirs is highly correlated in the VISCONTI study with subsequent control of infection following treatment interruption, and magnitude of immune activation determines the long-term outcomes of disease progression. Early treatment is beneficial to decrease both the size of reservoirs and systemic immune activation.
AL: You have accepted to cochair a session during the 2016 ISHEID where the search of an HIV cure and an HIV vaccine will be discussed. Why are these topics important for you, and are the right speakers picked up?
CP: HIV cure and HIV protective vaccine are our next strides.
HIV cure is the only track to escape HIV and its consequences for someone who is already infected.
On the other hand, HIV protective vaccine can guarantee prevention of HIV infection particularly for populations where there is a high risk of HIV transmission. Even if a vaccine only protects some people, it could still have a major impact on the rates of transmission via herd immunity. To control and ultimately end HIV globally, we need a powerful array of HIV prevention tools that are widely accessible to all who would benefit from them: ART, PrEP and HIV protective vaccine. Daniel Kuritzkes and Dan Barouch are referent speakers respectively in domains of HIV cure and HIV vaccine, and besides their outstanding presentations we always like to see the hope in their eyes.
Key words: HIV cure, HIV persistence, HIV reservoirs, HIV vaccine, ISHEID