Human Leukocyte Antigen (HLA) part 73

Hepatitis C Virus (HCV)

HLA associations with respect to hepatitis B virus and HCV infection susceptibility, protection, disease severity, interferon treatment  response and response to vaccination have been intensively investigated across the global population. The associations between HLA class I antigens and the outcome of HCV infection are are extensively investegated in different ethnic populations, and the reported associations showed ethnic and geographical differences sometimes with contradictory results. In the same time, there is a striking concordance between several of the HLA alleles associated with clearance   in both HIV and HCV infection including, in particular, HLA-B27. Other associations with HLA-B57 and HLA B08DR3 are less consistent  and may relate to differences in viral sequences in certain subpopulations.

Human Leukocyte Antigen (HLA) part 72

Moreover, recent study by Elahi and Horton provided novel insights into the role of T regs in chronic viral infection. This study showed that HIV-specific CD8 T cells restricted by protective HLA-B27/B57 alleles are much more resistant to T reg-mediated suppression than CD8 T cells restricted by non-protective HLA alleles. This resistence to T reg suppression was because CD8 T cells restricted by protective HLA alleles upregulated low levels of T cell immunoglobulin Mucin Protein-3 where they encountered their antigen. Thus, T regs were not able to suppress  proliferation of these HIV-specific CD8 cytotoxic T lymphocyte through Tim-3:Galactine-9 interaction. In contrast, HIV-specific CD8 cytotoxic T lymphocyte restricted by non-protective allels upregulated high levels of Tim-3 when they encountered their antigen and were subsequently suppressed by  T regs. The lack of suppression of B27/B57-restricted cytotoxic T lymphocyte allows them to continue to proliferate and kill infected targets during chronic infection, which may account for delayed disease progression in persons with protective alleles

Human Leukocyte Antigen (HLA) part 71

Therefore, there must be additionally immunological mechanisms that contribute to the protective effect of these HLA alleles in HIV and HCV infection. Several  immunological mechanisms have been suggested contributing to protection by HLA-B-27 including CD8 T cell polyfunctionality (indicated by simultaneous  production of multiple antiviral cytokines) and functional avidity (the sensitivity of CD8 T cells to antigenic stimulation), thymic selection of CD8 T cell precursor (HLA class I alleles that bind few  self-peptides are associated with a greater CD8 T cell precursor   \repertoir and broader cross-reactivity of CD8 T cells, finally leading to superior viral control), specific T cell receptor repertoirs and clonotypes (the selection of T cell receptor clonotypes impact antiviral efficacy and the capacity  to cross-recognize viral variants and in HCV, limited  T cell receptor diversity has been linked to the evolution of viral escape mutations), efficient antigen processing (the amount of peptide produced by the antigen-processing machinery  correlated with magnitude  and requency of HIV and HCV-specific CD8 T cells responses) and evasion from T reg suppression (T regs are thought to suppress HIV and HCV-specific CD8 T cells) and thus contribute to CD8 T cell exhaution snd failure. It has been demonstrate, however, that HIV-specific CD8 T cells restricted by the protective HLA alleles B27 and B57 are not suppressed by T regs

Human Leukocyte Antigen (HLA) part 70

Kaslow et al. assesed the role of HLA class I alleles in HIV infection and found that HLA-B27 and B57 were strongly associated with slow progression to AIDS. Importantly, several independent studies have confirmed this finding, including a recent study that included more than 2700 patients with HIV infection. It is important to note, however, that HLA-B27 and B57 are not unique in their association with HIV control, but are rather extremes in an continuous spectrum of "protective" to "hazardous" HLA class I alleles. HLA-B27 is associated with low viral load and long-term non-progression in HIV infection as well as spontaneous clearance of hepatitis C infection. Recent studies  linked protection by HLA-B27 in HIV and HCV infection to virological mechanisms such as  complicated pathways of viral escape from immunodominant HLA-B27-restricted virus-specific CD 8 T cell epitopes. This virological mechanisms may help to explain why CD8 T cell responses targeting certain  HIV and HCV-specific epitopes contribute to protection. However, they cannot explain why largely the same HLA class I alleles, including HLA-B27 and HLA-B57, are protective in unrelated viral infections.

Human Leukocyte Antigen (HLA) part 69

Overall, the data suggest that a broader range of HIV-1 peptides are recognized by HLA heterozygous individuals resulting in more efficient-specific cytotoxic T lymphocyte responses againt the pathogen. It may also take the virus a longer time to accumulate escape mutations in HLA heterozygous individuals relative to homozygous individuals. An alternative interpretation of the data  is based on a model of frequency-dependent selection  (or rare allele advantage), which argues that HIV adapts to HLA alleles that are common in the population. This alleles are most likely to be observed in HLA homozygotes. HLA heterozygoous individuals on the other hand are more likely to carry rare alleles (in combination with common alleles), to which the virus has not adapted as well, and therefore, individuals with these alleles are better able to contain the virus.

Human Leukocyte Antigen (HLA) part 68

The primary function of HLA molecules is to present foreign antigens to elicit T cell responses, so the number of distinc HLA allotypes expressed on the cell surface is directly related to the range of foreign antigens the host can present to T cells. Thus, individuals who are heterozygous at the HLA locus will be able to present a broader repertoire of antigenic peptides  to T cells  as compared to homozygotes, thereby exerting greater pressure on the pathogen  to escape  the cytotoxic T lymphocyte responses that may in turn affect pathogen fitness. Under this model, it would be expected that HLA homozygous individuals would progress more rapidly to AIDS than HLA heterozygous individuals after HIV infection. Indeed, a highly  significant association of HLA class I homozygosity with rapid progression to AIDS in both Caucasians and African Americans was demonstrated and the three  class I loci contributed independently to the association, and the effect was most pronounced in individuals who were homozygous at two or three.

Human Leukocyte Antigen (HLA) part 67

HIV infection typically manifest  with an acute viral syndrome, followed by a period of immune control with relatively low viral loads  and stable CD4 T cell counts. After this asymptomatic  period of usually 8-10 years, viral loads increase, CD4 T cell counts drop and AIDS-defining  opportunistic infections or malignancies occur in untreated patients. There are, however, some patients who display a superior HIV control. These "elite controllers" or "long-term non-progessores" have low viral loads and remain asymptomatic even for decades before the onset of AIDS.