Clinical outcomes and immunological response to SARS-CoV-2 infection among people living with HIV

People living with HIV (PLWH) usually suffer from co-infections and co-morbidities including respiratory tract infections. SARS-CoV-2 has been reported to cause respiratory infections. There are uncertainties in the disease severity and immunological response among PLWH who are co-infected with COVID-19. This review outlines the current knowledge on the clinical outcomes and immunological response to SARS-CoV-2 among PLWH. Literature was searched in Google scholar, Scopus, PubMed, and Science Direct conforming with the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines from studies published from January 2020 to June 2023. A total of 81 studies from 25 countries were identified, and RT-PCR was used in confirming COVID-19 in 80 of the studies. Fifty-seven studies assessed risk factors and clinical outcomes in HIV patients co-infected with COVID-19. Thirty-nine of the studies indicated the following factors being associated with severe outcomes in HIV/SARS-CoV-2: older age, the male sex, African American race, smoking, obesity, cardiovascular diseases, low CD4+ count, high viral load, tuberculosis, high levels of inflammatory markers, chronic kidney disease, hypertension, diabetes, interruption, and delayed initiation of ART. The severe outcomes are patients’ hospitalization, admission at intensive care unit, mechanical ventilation, and death. Twenty (20) studies, however, reported no difference in clinical presentation among co-infected compared to mono-infected individuals. Immune response to SARS-CoV-2 infection was investigated in 25 studies, with some of the studies reporting high levels of inflammatory markers, T cell exhaustion and lower positive conversion rate of IgG in PLWH. There is scanty information on the cytokines that predisposes to severity among HIV/SARS-CoV-2 co-infected individuals on combined ART. More research work should be carried out to validate co-infection-related cytokines and/or immune markers to SARS-CoV-2 among PLWH.


Introduction
People living with HIV (PLWH) usually suffer from coinfections and co-morbidities including respiratory tract infections, renal impairment, hypertension, diabetes, obesity, hyperlipidemia, chronic viral hepatitis, and non-AIDSdefining malignancies among others [1,2].These coinfections and co-morbidities tend to limit the efficacy of the antiretroviral therapy [3].Respiratory tract infections are of a major concern due to the compromised immune state of PLWH that makes them vulnerable to severe diseases [4].
In 2019, the novel SARS-CoV-2, a new coronavirus broke out in China, also known as .As of September 2023, WHO reported 770,875,433 confirmed cases of COVID-19, and 6,959,316 deaths [5] spreading throughout the globe.SARS-CoV-2 has been reported to also cause more severe RTIs in HIV patients [6,7].Co-infections in humans have become a topic among researchers with wide interest to know their clinical importance [8,9].
PLWH infected with COVID-19, are thought to have more complicated clinical presentations due to immunodeficiency and immune imbalance [6].Research has reported COVID-19 in PLWH to be severe [10].Other studies however, indicated similarity in prevalence and deleterious outcomes among both the co-infected and mono-infected [11,12].Bhaskaran and others reported an increased COVID-19 mortality and morbidity risk among PLWH [13], but other researchers were not convinced about this assertion and cautioned its authenticity [14].
T cell immune activation and some cytokines play a role in HIV progression [15].COVID-19 infection has also been investigated to be associated with some immune profiles [16].This usually leads to a cytokine storm where cytokines are then released to control inflammation causing more white blood cells to accumulate, creating a cycle of inflammation thereby damaging the lung cells.This indicates that co-infections of these HIV/SARS-CoV-2 conditions among humans may lead to harmful immunological response and a poor prognosis of disease.
This review paper sought to outline the current knowledge of clinical outcomes and immunological response to SARS-CoV-2 infection among PLWH.It also sought to identify gaps in relation to this coinfection study.

Selection criteria
All studies reporting on clinical outcomes and immune response among PLWH co-infected with SARS-CoV-2 were included.All immunological studies with observational studies, cohort studies, case reports, randomized controlled trials, and case series were also included.All studies meeting the above stated criteria, published from January 2020 to June 2023 and in the English language were included.Studies that do not address clinical outcomes and immunological response among PLWH co-infected with COVID-19 were excluded from this review.Letters to editors, editorials, commentaries, and brief reports that did not report on any clinical data were excluded.Literature reviews, systematic review and meta-analysis data were excluded.
Living With HIV."We then applied extra filters to access articles on "Immunological Response" or "Immune Characterization" or "Immunological Profiles" or "T-Cell Activation and Cytokines Profiles" and "Outcomes."Also, eligible studies were identified by scanning references by manual search.

Study selection
Titles were imported into Endnotes for every search, and duplicates were eliminated.Titles and abstracts were used by two researchers to independently check records for eligibility.The complete texts of any publications that were thought to be possibly eligible were then retrieved, evaluated, and unanimously chosen to be included in the study.Conflicts were arbitrated by a third investigator or resolved by consensus.

Data extraction and synthesis
Extracted data were imputed into a table.All data were in English language.Studies were curated by sampling date, study design, study place, study participants, assay type, additional tests, author, and year of publication.

Results
Studies selection was done using PRISMA guidelines (Figure 1).Databases searches (Google scholar: 17,500, Scopus: 559, ScienceDirect: 2,475, PubMed: 612) identified a total of 21,146.Eighty-three (81) studies met the eligibility criteria after the selection process (Figure 1).Endnote Software was used to remove duplicates.Also, studies that did not meet the eligibility criteria in the initial screening were 21,031.Fifty-five (55) studies were excluded due to the following reasons: No methods (4), only abstract (8), systematic review, literature review, meta-analysis (3), Brief report (1), editorial (6) and commentary (5).A manual scanning of references resulted in 22 additional reports.Eighty-one studies were included in this analysis.

Characteristics of included studies
Studies were identified in 25 countries in this review with United State of America contributing 17 of the included studies.Other countries where studies were carried out included South Africa (12), Italy (10), China (9), Spain (7), United Kingdom (5), France (3), Russia (2) and Brazil (2).Only one study was identified in the following countries (Korea, UAE, Iran, Germany, Japan, Guinea Bissau, Netherlands, Taiwan, Sweden, Israel, Belgium, Zambia, and Indonesia).Study participants included HIV patients, HIV naïve groups, COVID-19 patients.All studies were conducted among HIV patients.RT-PCR was used in confirming human coronaviruses in 99% of the studies.ELISA techniques were also used in 14 of the studies, followed by flow cytometry (n = 9), neutralization assay (n = 5), ELISpot (n = 4).
Fifty-seven studies have assessed clinical outcomes in HIV patients that were co-infected with SARS-CoV-2 (Table 1).Immune response to COVID-19 infection was investigated by 25 studies (Table 2).18 studies were made up of brief reports, case reports and editorials with clinical and laboratory data.All the studies were carried out from 2020 to 2023.
Thirty (38) studies reported the following risk factors as associated with severity of diseases (Table 1).This includes older age, higher BMI, male sex, deprivation, ethnicity, obesity, smoking, Tuberculosis, chronic kidney disease, higher inflammatory markers, diabetes, cardiovascular disease, lung cancer, African American, high viral load, low CD4 + count, high neutrophil-lymphocyte ratio, discontinued ART usage and some ART regimen.Twenty studies however indicated that clinical presentations among the co-infected were the same as the general population therefore there was low risk of disease severity (Table 1).
Twenty-five studies looked at immunological responses (Table 2), out of which four suggested that high inflammatory markers and immune dysregulation are linked to severity of disease and death among people who are coinfected with HIV/ SARS-CoV-2 and are on ART, even though the ART is supposed to help with HIV viral suppression and immune reconstitution [17][18][19][20][21][22].HIV/SARS-CoV-2 individuals with higher proinflammatory markers such as C-reactive protein (CRP), IL-8, IL-6 presented with disease severity and higher mortality than those who recovered [17].Three other studies on co-infections linked reduction of T cell numbers to increased IL-6, IL-8, and CRP levels, causing a cytokine storm [23][24][25].Among the coinfected individuals, unsuppressed HIV hampers T cell crossrecognition and responses to SARS-CoV-2 infection, and thereby leading to severe outcomes [26,27].The presymptom and post recovery CD4 + , and CD8 + counts showed no significant difference between PLWH and HIV negative individuals who are infected with SARS-CoV-2 [28].PLWH saw a brief decline in CD4 + , and CD8 + counts during the acute phase of COVID-19 with the CD4+/CD8+ ratio remaining unchanged [11,28].
Most of the studies were either retrospective or prospective with one time point sample collection, therefore, no subsequent CD4 + counts and viral loads to determine relationship with clinical outcomes.Two of the studies were longitudinal with one study investigating two waves of SARS-CoV-2 infection [26] and the other following up for a period of 3 months on HIV/SARS-CoV-2 patients [12].Snyman et al., indicated in their study that anti-SARS-CoV-2 IgM, IgG, and IgA levels in non-HIV individuals and PLWH on full HIV suppression on ART have similar seroconversion rates [12].The conversion rate of anti-SARS-CoV-2 IgG was lower and quickly lost in PLWH as compared to HIV negative persons who are SARS-CoV-2 positive [29][30][31].Three of the studies indicated that slower generation of anti SARS CoV2 antibodies were attributed to increased COVID-19 severity among PLWH [32][33][34].

Discussion
We conducted a scoping review to assess specific COVID-19 clinical outcomes and immune response in patients with human immunodeficiency virus (PLWH) and identify gaps.Hospitalisation risk, intensive care unit admission, mechanical ventilation and mortality were the four categories identified as clinical outcomes.Our review showed varied reports on risk of hospitalisation, ICU admission, mechanical ventilation and mortality in cohort studies, case series, and case reports.PLWH who died exhibited higher levels of soluble immune activation and inflammation markers, which are linked to disease severity in COVID-19 [22].Individuals with nonsuppressed HIV viremia have reported lower levels of antibodies against SARS-CoV-2 in their humoral response [35].Some studies however, associated low risk of hospitalization and death to Tenofovir usage as compared to those on other regimen [35][36][37].
Immune response to SARS-CoV-2 infection among PLWH on ART [38].ART may also reduce the severity of COVID-19 through immunological reconstitution, although these effects have not yet been confirmed [10,36,39].PLWH with mild COVID-19 presentation, in the presence of high proinflammatory markers, suggested that certain antiretroviral drugs were protective against severity of COVID-19 disease [20].A study in Russia among 376 HIV/COVID-19 patients (171 without ART and 205 with ART) suggested that elevated anti-inflammatory markers such as IL-10 and TGFβ, reduced CD4+/CD8+ cell ratios led to an increase in exhausted T cells in ART naïve patients.This led to Adverse Respiratory Distress Syndrome among the ART naïve group [32].Sharov also reiterated that in the presence of uninterrupted ART, HIV patients do not progress to severe SARS-CoV-2 infection [32].Other studies hypothesized that specific ART (NRTIs, NNRTIs and PI) predisposes to severe COVID-19 but no conclusive findings have been made because of studies involving smaller sample size and inconsistent cases and reports [40,41].
Some HIV proteins have been reported to inhibit effective IFNα signalling by degrading certain components of the JAK/ STAT signalling pathway like STAT1 and STAT3 [50].The impaired JAK/STAT signalling pathway is however restored in the presence of uninterrupted combined Antiretroviral therapy (cART) for more than 6 months [51].Per our search, we found one study available on HIV/COVID-19 signalling pathway that investigated STAT3 but did not look at other STAT pathways [52], and therefore creates a gap that needs to be researched.Understanding the viral coinfection, immune response, and signalling pathway dynamics will help identify particulate markers that predisposes to severity of disease.

Oxidative stress responses among HIV/ SARS-CoV-2 coinfection
Hyperactivation of STAT3 affect various biological and physiological functions, leading to oxidative stress (OxS) and poor prognosis of disease [22].Oxidative stress (OxS) comes about by accumulating reactive oxygen and nitrogen species, which are free radicals that causes injury to organs.Under physiological conditions, these OxS are wiped out by antioxidants especially glutathione (GSH) [53].Glutathione are endogenous intracellular antioxidants that neutralizes free radical released due to oxidative stress [54].Deficiency in GSH however, leads to high levels of OxS due to compromised antioxidant defences [55].Oxidative stress has been studied in HIV or SARS-CoV 2 alone with higher levels reported in each disease [55][56][57][58].There is however scanty information on oxidative stress among HIV/COVID-19 patients, hence the need to investigate if the presence of ART usage affects oxidative stress response.

Limitations
There is lack of information on cellular immunity in other hCoVs apart from COVID-19 co-infection.Cytokine have been studied extensively in HIV or COVID-19 alone but not as a coinfection.The oxidative stress levels among HIV/SARS-CoV-2 co-infection are yet to be studied although research has been done for other co-morbidities or co-infections.

Conclusion
This study highlights the paucity of clinical and immunological data on HIV/SARS-CoV-2 co-infection in sub-Saharan Africa, even though this region has the highest HIV prevalence.Review shows conflicting reports on severity of the co-infection.HIV/SARS-CoV-2 severity and outcomes appear to be worse, when coexisting age-related comorbidities and CD4 + T-cell depletion is present.Discontinued or no evidence of ART usage have also been shown to increase disease severity, which needs to be studied further to ascertain its authenticity.
CD4 + T cell lymphopenia in both diseases is influenced by various mechanisms including direct attacks, immune activation, and redistribution of CD4 + T cells.Cytokines investigation will help identify markers that are implicated in disease severity among HIV/SARS-CoV-2 patients.Further investigation is needed to confirm co-infection-associated

TABLE 1 (
Continued) Summary of clinical outcomes on HIV and SARS-CoV-2 co-infection studies and their spatial distribution.

TABLE 1 (
Continued) Summary of clinical outcomes on HIV and SARS-CoV-2 co-infection studies and their spatial distribution.

TABLE 1 (
Continued) Summary of clinical outcomes on HIV and SARS-CoV-2 co-infection studies and their spatial distribution.

TABLE 1 (
Continued) Summary of clinical outcomes on HIV and SARS-CoV-2 co-infection studies and their spatial distribution.

TABLE 1 (
Continued) Summary of clinical outcomes on HIV and SARS-CoV-2 co-infection studies and their spatial distribution.

TABLE 1 (
Continued) Summary of clinical outcomes on HIV and SARS-CoV-2 co-infection studies and their spatial distribution.

TABLE 1 (
Continued) Summary of clinical outcomes on HIV and SARS-CoV-2 co-infection studies and their spatial distribution.

TABLE 2 (
Continued) Summary of immunological response on HIV and SARS-CoV-2 co-infection studies and their spatial distribution.

TABLE 2 (
Continued) Summary of immunological response on HIV and SARS-CoV-2 co-infection studies and their spatial distribution.