HLA Variation and SARS-CoV-2 Specific Antibody Response.

Differences in SARS-CoV-2-specific immune responses have been observed between individuals following natural infection or vaccination. In addition to already known factors, such as age, sex, COVID-19 severity, comorbidity, vaccination status, hybrid immunity, and duration of infection, inter-individual variations in SARS-CoV-2 immune responses may, in part, be explained by structural differences brought about by genetic variation in the human leukocyte antigen (HLA) molecules responsible for the presentation of SARS-CoV-2 antigens to T effector cells. While dendritic cells present peptides with HLA class I molecules to CD8+ T cells to induce cytotoxic T lymphocyte responses (CTLs), they present peptides with HLA class II molecules to T follicular helper cells to induce B cell differentiation followed by memory B cell and plasma cell maturation. Plasma cells then produce SARS-CoV-2-specific antibodies. Here, we review published data linking HLA genetic variation or polymorphisms with differences in SARS-CoV-2-specific antibody responses. While there is evidence that heterogeneity in antibody response might be related to HLA variation, there are conflicting findings due in part to differences in study designs. We provide insight into why more research is needed in this area. Elucidating the genetic basis of variability in the SARS-CoV-2 immune response will help to optimize diagnostic tools and lead to the development of new vaccines and therapeutics against SARS-CoV-2 and other infectious diseases.

Targeted capture enrichment and sequencing identifies HLA variants associated with the severity of COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is currently a global pandemic. The pathogenesis of severe COVID-19 has been widely investigated, but it is still unclear. Human leukocyte antigen (HLA) plays a central role in immune response, and its variants might be related to COVID-19 progression and severity. OBJECTIVE: To investigate the hypothesis that individual HLA variations could alter the course of COVID-19 and might be associated with the severity of COVID-19. METHODS: In this study, we conducted an HLA targeted capture enrichment and sequencing of severe COVID-19 patients matched to mild cases. A total of 16 COVID-19 patients, confirmed by SARS-CoV-2 viral RNA polymerase-chain-reaction (PCR) test and chest computed tomography (CT) scan, were enrolled in this study. The HLA targeted capture enrichment and sequencing were conducted. HLA typing was performed by comparing contigs with IPD-IMGT/HLA Database. RESULTS: In this study, 139 four-digit resolution HLA alleles were acquired. The results showed that HLA-DRB3*01:01 allele was significantly associated with the severity of COVID-19 (odds ratio [OR] = 27.64, 95% confidence interval [CI] = 1.35-560.50, P = 0.0064). And HLA-K*01:01 might be a potential risk factor for COVID-19 severity (OR = 0.11, 95% CI = 0.017-0.66, P = 0.019), but HLA-K*01:02 might be a protective factor (OR = 7.50, 95% CI = 1.48-37.92, P = 0.019). CONCLUSION: Three non-classical HLA alleles, including HLA-DRB3*01:01, HLA-K*01:01, HLA-K*01:02 were identified to be associated with the severity of COVID-19 by comparing mild and severe patients. The current findings would be helpful for exploring the influence of HLA gene polymorphisms on the development and severity of COVID-19.

Non-classical HLA class I molecules and their potential role in viral infections.

Human Leukocyte Antigens (HLA) are classified in three different classes I, II and III, and represent the key mediators of immune responses, self-tolerance development and pathogen recognition. Among them, non-classical subtypes (HLA-Ib), e.g. HLA-E and HLA-G, are characterize by tolerogenic functions that are often exploited by viruses to evade the host immune responses. In this perspective, we will review the main current data referred to HLA-G and HLA-E and viral infections, as well as the impact on immune response. Data were selected following eligibility criteria accordingly to the reviewed topic. We used a set of electronic databases (Medline/PubMed, Scopus, Web of Sciences (WOS), Cochrane library) for a systematic search until November 2022 using MeSH keywords/terms (i.e. HLA, HLA-G, HLA-E, viral infection, SARS-CoV-2, etc.…). Recent studies support the involvement of non-classical molecules, such as HLA-E and HLA-G, in the control of viral infection. On one side, viruses exploit HLA-G and HLA-E molecule to control host immune activation. On the other side, the expression of these molecules might control the inflammatory condition generated by viral infections. Hence, this review has the aim to summarize the state of art of literature about the modulation of these non-classical HLA-I molecules, to provide a general overview of the new strategies of viral immune system regulation to counteract immune defenses.

The role of the HLA allelic repertoire on the clinical severity of COVID-19 in Canadians, living in the Saskatchewan province.

AIMS: The HLA system has been implicated as an underlying determinant for modulating the immune response to SARS-CoV-2. In this study, we aimed to determine the association of patients' HLA genetic profiles with the disease severity of COVID-19 infection. METHODS: Prospective study was conducted on COVID-19 patients (n = 40) admitted to hospitals in Saskatoon, Canada, between March and December 2020. Next-generation sequencing was performed on the patient samples to obtain high-resolution HLA typing profiles. The statistical association between HLA allelic frequency and disease severity was examined. The disease severity was categorized based on the length of hospital stay and intensive care needs or demise during the hospital stay. RESULTS: HLA allelic frequencies of the high and low-severity cohorts were normalized against corresponding background allelic frequencies. In the high-severity cohort, A*02:06 (11.8-fold), B*51:01 (2.4-fold), B*15:01(3.1-fold), C*01:02 (3.3-fold), DRB1*08:02 (31.2-fold), DQ*06:09 (11-fold), and DPB1*04:02(4-fold) were significantly overrepresented (p < 0.05) making these deleterious alleles. In the low-severity cohort, A*24:02 (2.8-fold), B*35:01 (2.8-fold), DRB1*04:07 (5.3-fold), and DRB1*08:11 (22-fold) were found to be significantly overrepresented (p < 0.05) making these protective alleles. These above alleles interact with NK cell antiviral activity via the killer immunoglobulin-like receptors (KIR). The high-severity cohort had a higher predilection for HLA alleles associated with KIR subgroups; Bw4-80I (1.1-fold), and C1 (1.6-fold) which promotes NK cell inhibition, while the low-severity cohort had a higher predilection for Bw4-80T (1.6-fold), and C2 (1.6-fold) which promote NK cell activation. CONCLUSION: In this study, the HLA allelic repository with the distribution of deleterious and protective alleles was found to correlate with the severity of the clinical course in COVID-19. Moreover, the interaction of specific HLA alleles with the KIR-associated subfamily modulates the NK cell-mediated surveillance of SARS-CoV-2. Both deleterious HLA alleles and inhibitory KIR appear prominently in the severe COVID-19 group focusing on the importance of NK cells in the convalescence of COVID-19.

A systemic review of T-cell epitopes defined from the proteome of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection remains in a global pandemic, and no eradicative therapy is currently available. Host T cells have been shown to play a crucial role in the antiviral immune protection and pathology in Coronavirus disease 2019 (COVID-19) patients; thus, identifying sufficient T-cell epitopes from the SARS-CoV-2 proteome can contribute greatly to the development of T-cell epitope vaccines and the precise evaluation of host SARS-CoV-2-specific cellular immunity. This review presents a comprehensive map of T-cell epitopes functionally validated from SARS-CoV-2 antigens, the human leukocyte antigen (HLA) supertypes to present these epitopes, and the strategies to screen and identify T-cell epitopes. To the best of our knowledge, a total of 1349 CD8+ T-cell epitopes and 790 CD4+ T-cell epitopes have been defined by functional experiments thus far, but most are presented by approximately twenty common HLA supertypes, such as HLA-A0201, A2402, B0702, DR15, DR7 and DR11 molecules, and 74-80% of the T-cell epitopes are derived from S protein and nonstructural protein. These data provide useful insight into the development of vaccines and specific T-cell detection systems. However, the currently defined T-cell epitope repertoire cannot cover the HLA polymorphism of major populations in an indicated geographic region. More research is needed to depict an overall landscape of T-cell epitopes, which covers the overall SARS-CoV-2 proteome and global patients.

In-silico study of influence of HLA heterogeneity on CTL responses across ethnicities to SARS-CoV-2.

Differences in outcome to COVID-19 infection in different individuals is largely attributed to genetic heterogeneity leading to differential immune responses across individuals and populations. HLA is one such genetic factor that varies across individuals leading to differences in how T-cell responses are triggered against SARS-CoV-2, directly influencing disease susceptibility. HLA alleles that influence COVID-19 outcome, by virtue of epitope binding and presentation, have been identified in cohorts worldwide. However, the heterogeneity in HLA distribution across ethnic groups limits the generality of such association. In this study, we address this limitation by comparing the recognition of CTL epitopes across HLA genotypes and ethnic groups. Using HLA allele frequency data for ethnic groups from Allele Frequency Net Database (AFND), we construct synthetic populations for each ethnic group and show that CTL epitope strength varies across HLA genotypes and populations. We also observe that HLA genotypes, in certain cases, can have high CTL epitope strengths in the absence of top-responsive HLA alleles. Finally, we show that the theoretical estimate of responsiveness and hence protection offered by a HLA allele is bound to vary across ethnic groups, due to the influence of other HLA alleles within the HLA genotype on CTL epitope recognition. This emphasizes the need for studying HLA-disease associations at the genotype level rather than at a single allele level.

Human leukocyte antigen class II gene diversity tunes antibody repertoires to common pathogens.

Allelic diversity of human leukocyte antigen (HLA) class II genes may help maintain humoral immunity against infectious diseases. In this study, we investigated germline genetic variation in classical HLA class II genes and employed a systematic, unbiased approach to explore the relative contribution of this genetic variation in the antibody repertoire to various common pathogens. We leveraged a well-defined cohort of 800 adults representing the general Arab population in which genetic material is shared because of the high frequency of consanguineous unions. By applying a high-throughput method for large-scale antibody profiling to this well-defined cohort, we were able to dissect the overall effect of zygosity for classical HLA class II genes, as well as the effects associated with specific HLA class II alleles, haplotypes and genotypes, on the antimicrobial antibody repertoire breadth and antibody specificity with unprecedented resolution. Our population genetic studies revealed that zygosity of the classical HLA class II genes is a strong predictor of antibody responses to common human pathogens, suggesting that classical HLA class II gene heterozygosity confers a selective advantage. Moreover, we demonstrated that multiple HLA class II alleles can have additive effects on the antibody repertoire to common pathogens. We also identified associations of HLA-DRB1 genotypes with specific antigens. Our findings suggest that HLA class II gene polymorphisms confer specific humoral immunity against common pathogens, which may have contributed to the genetic diversity of HLA class II loci during hominine evolution.

Surprise virus tied to pediatric hepatitis cases.

Two viruses plus a child's genetic background may explain a recent surge in the United Kingdom.

SARS-CoV-2 mRNA vaccination is not associated with the induction of anti-HLA or non-HLA antibodies.

BACKGROUND: SARS-CoV-2 vaccination is strongly recommended in kidney transplant recipients (KTR) and dialysis patients. Whether these vaccinations may trigger alloantibodies, is still debated. METHODS: In the current study we evaluated the effect of SARS-CoV-2 mRNA vaccines on anti-Human Leukocyte Antigen (HLA) and 60 anti-non-HLA antibody profiles in clinically stable KTR and dialysis patients. In total, we included 28 KTR, 30 patients on haemodialysis, 25 patients on peritoneal dialysis and 31 controls with a positive seroresponse 16-21 days after the first dose of either the SARS-CoV-2 mRNA BNT162b2 or mRNA-1273 vaccine. Both anti-HLA and anti-non-HLA antibodies were determined prior to vaccination and 21 to 35 days after the second vaccine dose. RESULTS: Overall, the proportion of patients with detectable anti-HLA antibodies was similar before and after vaccination (class I 14% vs. 16%, p = 0.48; class II 25% before and after vaccination). After vaccination, there was no pattern in 1) additionally detected anti-HLA antibodies, or 2) the levels of pre-existing ones. Additional anti-non-HLA antibodies were detected in 30% of the patients, ranging from 1 to 5 new anti-non-HLA antibodies per patient. However, the clinical significance of anti-non-HLA antibodies is still a matter of debate. To date, only a significant association has been found for anti-non-HLA ARHGDIB antibodies and long-term kidney graft loss. No additionally developed anti-ARHGDIB antibodies or elevated level of existing anti-ARHGDIB antibodies was observed. CONCLUSION: The current data indicate that SARS-CoV-2 mRNA vaccination does not induce anti-HLA or anti-non-HLA antibodies, corroborating the importance of vaccinating KTR and dialysis patients.

Human Leukocyte Antigen (HLA) System: Genetics and Association with Bacterial and Viral Infections.

The human leukocyte antigen (HLA) system is one of the most crucial host factors influencing disease progression in bacterial and viral infections. This review provides the basic concepts of the structure and function of HLA molecules in humans. Here, we highlight the main findings on the associations between HLA class I and class II alleles and susceptibility to important infectious diseases such as tuberculosis, leprosy, melioidosis, Staphylococcus aureus infection, human immunodeficiency virus infection, coronavirus disease 2019, hepatitis B, and hepatitis C in populations worldwide. Finally, we discuss challenges in HLA typing to predict disease outcomes in clinical implementation. Evaluation of the impact of HLA variants on the outcome of bacterial and viral infections would improve the understanding of pathogenesis and identify those at risk from infectious diseases in distinct populations and may improve the individual treatment.

HLA variation and antigen presentation in COVID-19 and SARS-CoV-2 infection.

The extraordinary variation of the human leukocyte antigen (HLA) molecules is critical for diversifying antigen presentation to T cells. Coupled with the rise of novel strains and rapidly evolving immune evasion by SARS-CoV-2 proteins, HLA-mediated immunity in COVID-19 is critically important but far from being fully understood. A growing number of studies have found the association of HLA variants with different COVID-19 outcomes and that HLA genotypes associate with differential immune responses against SARS-CoV-2. Prediction studies have shown that mutations in multiple viral strains, most concentrated in the Spike protein, affect the affinity between these mutant peptides and HLA molecules. Understanding the impact of this variation on T-cell responses is critical for comprehending the immunogenic mechanisms in both natural immunity and vaccine development.

Allelic imbalance of HLA-B expression in human lung cells infected with coronavirus and other respiratory viruses.

The human leucocyte antigen (HLA) loci have been widely characterized to be associated with viral infectious diseases using either HLA allele frequency-based association or in silico predicted studies. However, there is less experimental evidence to link the HLA alleles with COVID-19 and other respiratory infectious diseases, particularly in the lung cells. To examine the role of HLA alleles in response to coronavirus and other respiratory viral infections in disease-relevant cells, we designed a two-stage study by integrating publicly accessible RNA-seq data sets, and performed allelic expression (AE) analysis on heterozygous HLA genotypes. We discovered an increased AE pattern accompanied with overexpression of HLA-B gene in SARS-CoV-2-infected human lung epithelial cells. Analysis of independent data sets verified the respiratory virus-induced AE of HLA-B gene in lung cells and tissues. The results were further experimentally validated in cultured lung cells infected with SARS-CoV-2. We further uncovered that the antiviral cytokine IFNß contribute to AE of the HLA-B gene in lung cells. Our analyses provide a new insight into allelic influence on the HLA expression in association with SARS-CoV-2 and other common viral infectious diseases.

HLA repertoire of 115 UAE nationals infected with SARS-CoV-2.

The class I and class II Human Leucocyte Antigens (HLA) are an integral part of the host adaptive immune system against viral infections. The characterization of HLA allele frequency in the population can play an important role in determining whether HLA antigens contribute to viral susceptibility. In this regard, global efforts are currently underway to study possible correlations between HLA alleles with the occurrence and severity of SARS-CoV-2 infection. Specifically, this study examined the possible association between specific HLA alleles and susceptibility to SARS-CoV-2 in a population from the United Arab Emirates (UAE). The frequencies of HLA class I (HLA-A, -B, and -C) and HLA class II alleles (HLA-DRB1 and -DQB1); defined using Next Generation Sequencing (NGS); from 115 UAE nationals with mild, moderate, and severe SARS-CoV-2 infection are presented here. HLA alleles and supertypes were compared between hospitalized and non-hospitalized subjects. Statistical significance was observed between certain HLA alleles and supertypes and the severity of the infection. Specifically, alleles HLA-B*51:01 and HLA-A*26:01 showed a negative association (suggestive of protection), whilst genotypes HLA-A*03:01, HLA-DRB1*15:01, and supertype B44 showed a positive association (suggestive of predisposition) to COVID-19 severity. The results support the potential use of HLA testing to differentiate between patients who require specific clinical management strategies.

COVID-19 Pandemic: Escape of Pathogenic Variants and MHC Evolution.

We propose a new hypothesis that explains the maintenance and evolution of MHC polymorphism. It is based on two phenomena: the constitution of the repertoire of naive T lymphocytes and the evolution of the pathogen and its impact on the immune memory of T lymphocytes. Concerning the latter, pathogen evolution will have a different impact on reinfection depending on the MHC allomorph. If a mutation occurs in a given region, in the case of MHC allotypes, which do not recognize the peptide in this region, the mutation will have no impact on the memory repertoire. In the case where the MHC allomorph binds to the ancestral peptides and not to the mutated peptide, that individual will have a higher chance of being reinfected. This difference in fitness will lead to a variation of the allele frequency in the next generation. Data from the SARS-CoV-2 pandemic already support a significant part of this hypothesis and following up on these data may enable it to be confirmed. This hypothesis could explain why some individuals after vaccination respond less well than others to variants and leads to predict the probability of reinfection after a first infection depending upon the variant and the HLA allomorph.

Three Specific Potential Epitopes That Could Be Recognized by T Cells of Convalescent COVID-19 Patients Were Identified From Spike Protein.

The current coronavirus disease 2019 (COVID-19) vaccines are used to prevent viral infection by inducing neutralizing antibody in the body, but according to the existing experience of severe acute respiratory syndrome coronavirus (SARS) infection, T-cell immunity could provide a longer durable protection period than antibody. The research on SARS-CoV-2-specific T-cell epitope can provide target antigen for the development and evaluation of COVID-19 vaccines, which is conducive to obtain COVID-19 vaccine that can provide long-term protection. For screening specific T-cell epitopes, a SARS-CoV-2 S protein peptide library with a peptide length of 15 amino acids was synthesized. Through flow cytometry to detect percentage of IFN-γ+ T cells after mixed COVID-19 convalescent patients' peripheral blood mononuclear cell with peptide library, seven peptides (P77, P14, P24, P38, P48, P74, and P84) that can be recognized by the T cells of COVID-19 convalescent patients were found. After excluding the nonspecific cross-reactions with unexposed population, three SARS-CoV-2-specific T-cell potential epitopes (P38, P48, and P84) were finally screened with the positive reaction rates between 15.4% and 48.0% in COVID-19 convalescent patients. This study also provided the HLA allele information of peptide-positive-response COVID-19 convalescent patients, thus predicting the population coverage of these three potential epitopes. Some HLA alleles showed higher frequency of occurrence in COVID-19 patients than in total Chinese population but no HLA alleles related to the T-cell peptide response and the severity of COVID-19. This research provides three potential T-cell epitopes that are helpful for the design and efficacy evaluation of COVID-19 vaccines. The HLA information provided by this research supplies reference significance for subsequent research such as finding the relation of HLA genotype with disease susceptibility.

Association of HLA gene polymorphism with susceptibility, severity, and mortality of COVID-19: A systematic review.

HLA is crucial for appropriate immune responses in several viral infections, as well as in severe acute respiratory syndrome coronavirus-2 (SARS CoV-2). The unpredictable nature of Coronavirus Disease 19 (COVID-19), observed in both inter-individual and inter-population level, raises the question, to what extent the HLA, as part of host genetic factors, contribute to disease susceptibility and prognosis. We aimed to identify significant HLAs, those were investigated till now, for their association with COVID-19. Three databases were searched (PubMed, Cochrane library, and Web of Science) and articles published between January 2020 and May 2021 were included for in-depth analysis. Two separate teams including four observers independently extracted the summary data, with discrepancies resolved by consensus. This study is registered with PROSPERO (CRD42021251670). Of 1278 studies identified, 36 articles were included consisting of 794,571 participants. Countries from the European region appeared in the highest number of studies and vice versa for countries from South East Asia. Among 117 significantly altered alleles, 85 (72.65%) were found to have a positive correlation with COVID-19 and 33 (27.35%) alleles were observed having a negative correlation. HLA A*02 is the most investigated allele (n = 18) and showed contradictory results. Non-classical HLA E was explored by only one study and it showed that E*01:01 is associated with severity. Both in silico and wet lab data were considered and contrasting results were found from two approaches. Although several HLAs depicted significant association, nothing conclusive could be drawn because of heterogeneity in study designs, HLA typing methods, and so forth. This systematic review shows that, though HLAs play role in COVID-19 susceptibility, severity, and mortality, more uniformly designed, interrelated studies with the inclusion of global data, for use in evidence-based medicine are needed.

TCR meta-clonotypes for biomarker discovery with tcrdist3 enabled identification of public, HLA-restricted clusters of SARS-CoV-2 TCRs.

T-cell receptors (TCRs) encode clinically valuable information that reflects prior antigen exposure and potential future response. However, despite advances in deep repertoire sequencing, enormous TCR diversity complicates the use of TCR clonotypes as clinical biomarkers. We propose a new framework that leverages experimentally inferred antigen-associated TCRs to form meta-clonotypes - groups of biochemically similar TCRs - that can be used to robustly quantify functionally similar TCRs in bulk repertoires across individuals. We apply the framework to TCR data from COVID-19 patients, generating 1831 public TCR meta-clonotypes from the SARS-CoV-2 antigen-associated TCRs that have strong evidence of restriction to patients with a specific human leukocyte antigen (HLA) genotype. Applied to independent cohorts, meta-clonotypes targeting these specific epitopes were more frequently detected in bulk repertoires compared to exact amino acid matches, and 59.7% (1093/1831) were more abundant among COVID-19 patients that expressed the putative restricting HLA allele (false discovery rate [FDR]<0.01), demonstrating the potential utility of meta-clonotypes as antigen-specific features for biomarker development. To enable further applications, we developed an open-source software package, tcrdist3, that implements this framework and facilitates flexible workflows for distance-based TCR repertoire analysis.

Effect of BCG Revaccination on Occupationally Exposed Medical Personnel Vaccinated against SARS-CoV-2.

The production of specific neutralizing antibodies by individuals is thought to be the best option for reducing the number of patients with severe COVID-19, which is the reason why multiple vaccines are currently being administered worldwide. We aimed to explore the effect of revaccination with BCG, on the response to a subsequent anti-SARS-CoV-2 vaccine, in persons occupationally exposed to COVID-19 patients. Two groups of 30 randomized participants were selected: one group received a BCG revaccination, and the other group received a placebo. Subsequently, both groups were vaccinated against SARS-CoV-2. After each round of vaccination, the serum concentration of Th1/Th2 cytokines was determined. At the end of the protocol, neutralizing antibodies were determined and the HLA-DRB loci were genotyped. The participants from the BCG group and anti-SARS-CoV-2 vaccine group had increased serum cytokine concentrations (i.e., IL-1ß, IL-4, IL-6, IL-12p70, IL-13, IL-18, GM-CSF, INF-γ, and TNF-α) and higher neutralizing antibody titers, compared to the group with Placebo-anti-SARS-CoV-2. Twelve HLA-DRB1 alleles were identified in the Placebo-anti-SARS-CoV-2 group, and only nine in the group revaccinated with BCG. The DRB1*04 allele exhibited increased frequency in the Placebo-anti-SARS-CoV-2 group; however, no confounding effects were found with this allele. We conclude that revaccination with BCG synergizes with subsequent vaccination against SARS-CoV-2 in occupationally exposed personnel.

SARS Cov-2 vaccination induces de novo donor-specific HLA antibodies in a renal transplant patient on waiting list: A case report.

The ability of COVID-19 vaccination to induce anti-HLA antibodies (Abs) formation in renal transplant candidates is not well studied. A 42-year-old man on a renal transplant waitlist, with no sensitization history, was tested for DSA before and after COVID-19 vaccination. Patient has consistently tested negative for COVID-19 virus. Eighteen days after receiving first dose of mRNA-based vaccine, flow cytometry crossmatch (FCXM) was strongly positive with de novo donor-specific Ab (dnDSA) against B57 and de novo non-DSA against B58. Before vaccination, preliminary FCXM was negative with no anti-HLA Abs. This event prompted the transplant team to cancel the surgery. COVID-19 vaccination could be associated with anti-HLA Abs formation in renal patients on waitlists that could affect future transplantability.

Host factors: Implications in immunopathogenesis of COVID-19.

Coronavirus disease 2019 (COVID-19) is a viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is more serious in people with underlying diseases, but the cause of healthy people with progressive disease is largely unknown. Host genetic factors such as ACE2 variants, IFITM-3, HLA, TMRSS2, and furin polymorphisms appear to be one of the agents involved in the progression of the COVID-19 and outcome of the disease. This review discusses the general characteristics of SARS-CoV-2, including viral features, receptors, cell entry, clinical findings, and the main human genetic factors that may contribute to the pathogenesis of COVID-19 and get the patients' situation more complex. Further knowledge in this context may help to find a way to prevent and treat this viral pneumonia.