Role of Zinc Supplementation in Immunological Non-responders HIV Individuals: Exploring Pathways for Persistent Inflammation

Studies of people living with HIV show that although antiretroviral treatments (ART) decreases inflammation, a number of inflammatory markers remain persistently elevated and this chronic inflammation can play an important role in cardiovascular disease (CVD). Moreover, some individuals with HIV initiating ART do not recover Cluster of differentiation 4 (CD4+) T-cells count as expected, and are described as Immunological Non-Responders (INRs). INRs present with severely altered immunological functions, including malfunction and diminished production of cells within lymphopoietic tissue, perturbed frequencies of immune regulators such as regulatory T cells and Th17 cells, and increased immune activation, immunosenescence, and apoptosis. Importantly, INRs have an increased risk of morbidity and mortality compared to HIV-infected patients with an optimal immune reconstitution. Our group has demonstrated how this group responds poorly to messenger RNA (mRNA) vaccination against Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV2) showing an impaired immune function among these individuals.

However, the definition of Immunological Non-Responders (INRs) suffers from lack of consensus impeding the comparison of findings. There seems to be agreement that an adequate immune response to antiretroviral treatment should include a CD4+ cells count more than 500 cells/μL, mainly because HIV-infected patients with this level of immune restoration have a morbidity and mortality rate approaching or comparable to those of HIV negative individuals. Patients with CD4+ cell counts <500 cells/μL are consequently classified as inadequate responders, included in the INRs group. And, although they are a group poorly described, their morbidity and mortality seem to be more similar to INRs than to adequate responders.

The underlying mechanism that explains INRs phenomena is not well understood. Several hypotheses have been raised as an older age, a long duration of HIV infection prior to antiretroviral treatment, co-infection with hepatitis C, and a low CD4 nadir predispose to immunological nonresponse. The CD4 nadir specifically appears to be critical for the recovery of CD4+ cells. However, none of these factors provide a full explanation for the lack of immune reconstitution in INRs. Probably this is the consequence of several factors and its interaction. Interestingly, low plasma zinc levels and inadequate zinc intake were found in up 50% of participants in several cohorts of HIV infected adults, and were independently associated with faster HIV disease progression and increased mortality. Zinc deficiency reduces generation of T-cells, depresses humoral and cell-mediated immunity, leads to lymphopenia, and thymic atrophy, and increases the frequency and number of infections. Thus, the zinc status could also have a role in the mechanisms involved in INRs.

Zinc in viral infection Zinc is an essential trace element for both host and pathogens. In order to grow, pathogens require zinc. Thus, zinc is a structural cofactor of viral proteins and certain viruses have developed strategies to alter cellular zinc homeostasis on its benefit. On the other hand, there is extensive evidence that zinc can prevent viral replication and lower cellular invasion (eg. Rhinovirus, Hepatitis C,SARS-CoV2).

Remarkably, our team has shown that low zinc levels favor SARS-CoV2 expansion. These results might indicate either a direct anti-viral action against SARS-CoV2 or that the virus benefits from stress conditions caused by low levels of cellular zinc. Zinc supplementation has been shown to be beneficial when administering to Hepatitis B and Hepatitis C infected patients. Moreover, zinc-based nutritional immunity reduces diarrheal episodes and respiratory tract diseases. Remarkably, zinc supplementation for the common cold caused by rhino- and coronaviruses prevents it and reduces its duration, if the administration starts within 24h after the onset of symptoms. Thus, zinc supplementation has been proven beneficial against some viral infections. However, whether this was caused by improved local immune response or viral inhibition remains uncertain.