Virus-specific CD8+ T-cell responses better define HIV disease progression than HLA genotype.

HLA alleles B57/58, B27, and B35 have the strongest genetic associations with HIV-1 disease progression. The mechanisms of these relationships may be host control of HIV-1 infection via CD8(+) T-cell responses. We examined these immune responses in subjects from the Seattle Primary Infection Cohort with these alleles. CD8(+) T-cell responses to conserved HIV epitopes within B57/58 alleles (TW10 and KF11) and B27 alleles (KK10 and FY10) delayed declines in CD4(+) T-cell counts (4 to 8 times longer), while responses to variable epitopes presented by B35 alleles (DL9 and IL9) resulted in more rapid progression. The plasma viral load was higher in B57/58(+) and B27(+) subjects lacking the conserved B57/58- and B27-restricted responses. The presence of certain B57/58-, B27-, and B35-restricted HIV-specific CD8(+) T-cell responses after primary HIV-1 infection better defined disease progression than the HLA genotype alone, suggesting that it is the HIV-specific CD8(+) T cells and not the presence of a particular HLA allele that determine disease progression. Further, the most effective host CD8(+) T-cell responses to HIV-1 were prevalent within an HLA allele, represented a high total allele fraction of the host CD8(+) T-cell response, and targeted conserved regions of HIV-1. These data suggest that vaccine immunogens should contain only conserved regions of HIV-1.

Blepharoptosis and external ophthalmoplegia associated with long-term antiretroviral therapy.

BACKGROUND: Long-term antiretroviral therapy (ART) is associated with lipodystrophy, peripheral neuropathy, lactic acidosis, and myopathy. Blepharoptosis, without prior ART association, is usually caused by age-associated involutional ptosis, but it is also seen in mitochondrial myopathies with external ophthalmoplegia, cardiac conduction disturbances, and neurological impairments. METHODS: Patients presented over a 2-year period. Four patients underwent surgical blepharoptosis repair. RESULTS: Five human immunodeficiency virus type 1-infected patients (median age, 50 years; range, 46-53 years) who were receiving ART presented with severe blepharoptosis; 2 of these 5 also presented with external ophthalmoplegia. Findings included decreased palpebral fissure height (median, 6.5 mm; normal height, 9 mm), mildly impaired levator function (median, 10 mm; normal, >13 mm), and markedly decreased marginal reflex distance (median, 0.5 mm; normal, 4 mm). A greater advancement of the levator aponeurosis was required during surgical repair, a finding consistent more with myogenic than with involutional blepharoptosis. All patients had severe lipodystrophy, which preceded blepharoptosis by a median interval of 4.7 years (range, 2.8-5.7 years). Four patients also presented with peripheral neuropathy and metabolic abnormalities before the onset of blepharoptosis, and 3 had cardiac conduction disturbances. Patients received ART for a median of 7.8 years (range, 4.9-11.2 years), thymidine analogue-containing ART for a median of 7.1 years (range, 1.2-7.9 years), and protease inhibitor-containing ART for a median of 7.1 years (range, 4.9-8.9 years). CONCLUSIONS: We report the novel findings of blepharoptosis and external ophthalmoplegia in patients who are receiving ART. Ptosis was preceded by lipodystrophy with long-term use of both thymidine-analogue- and protease inhibitor-containing ART. The findings are most consistent with myogenic ptosis in a generalized mitochondrial myopathy syndrome. Clinicians should also be watchful for other potential myopathic ptosis-associated complications, including proximal weakness, dysphagia, deafness, and cardiac conduction disturbances.

Regional body fat distribution in HIV-infected patients with lipodystrophy.

BACKGROUND: Objective criteria for the assessment of patients with lipodystrophy syndrome in human immunodeficiency virus infection (LDHIV) have not emerged. METHODS: We compared regional body fat changes in 13 men with severe LDHIV on protease inhibitor-inclusive antiretroviral therapy with 13 control HIV-infected men using anthropometry, dual-energy X-ray absorptiometry (DEXA), and whole-body magnetic resonance imaging (MRI). RESULTS: LDHIV patients, compared with control subjects, had thinner gluteal, suprailiac, and triceps skinfolds (p < .01) and increased waist circumference (98 +/- 5 cm vs 86 +/- 9 cm, respectively; p = .0008). DEXA studies revealed reduced lower extremity fat (12 +/- 5% vs 22 +/- 9%; p = .0006), increased head and neck fat (18 +/- 3% vs 16 +/- 1%; p = .01), and increased proportion of total body fat in the trunk (65 +/- 7% vs 53 +/- 8%; p = .0005). MRI analysis revealed reduced thigh fat (12 +/- 5% vs 22 +/- 12%; p = .01), increased dorsocervical fat depth (47 +/- 24 mm vs 19 +/- 7 mm; p = .0009), and nearly significant increase in intra-abdominal fat (218 +/- 90 cm2 vs 157 +/- 70 cm2; p = .057). Interestingly, control subjects showed a positive relationship between intra-abdominal and dorsocervical fat (r= .57, p = .04), but the LDHIV patients showed a negative relationship (r= -.55, p = .05), suggesting a novel split phenotype among LDHIV patients of either dorsocervical or intra-abdominal fat accumulation. CONCLUSIONS: We conclude that MRI provides the best tools for definition of LDHIV syndrome and reveals variable phenotypes among LDHIV patients.

Superior control of HIV-1 replication by CD8+ T cells targeting conserved epitopes: implications for HIV vaccine design.

A successful HIV vaccine will likely induce both humoral and cell-mediated immunity, however, the enormous diversity of HIV has hampered the development of a vaccine that effectively elicits both arms of the adaptive immune response. To tackle the problem of viral diversity, T cell-based vaccine approaches have focused on two main strategies (i) increasing the breadth of vaccine-induced responses or (ii) increasing vaccine-induced responses targeting only conserved regions of the virus. The relative extent to which set-point viremia is impacted by epitope-conservation of CD8(+) T cell responses elicited during early HIV-infection is unknown but has important implications for vaccine design. To address this question, we comprehensively mapped HIV-1 CD8(+) T cell epitope-specificities in 23 ART-naïve individuals during early infection and computed their conservation score (CS) by three different methods (prevalence, entropy and conseq) on clade-B and group-M sequence alignments. The majority of CD8(+) T cell responses were directed against variable epitopes (p<0.01). Interestingly, increasing breadth of CD8(+) T cell responses specifically recognizing conserved epitopes was associated with lower set-point viremia (r = - 0.65, p = 0.009). Moreover, subjects possessing CD8(+) T cells recognizing at least one conserved epitope had 1.4 log10 lower set-point viremia compared to those recognizing only variable epitopes (p = 0.021). The association between viral control and the breadth of conserved CD8(+) T cell responses may be influenced by the method of CS definition and sequences used to determine conservation levels. Strikingly, targeting variable versus conserved epitopes was independent of HLA type (p = 0.215). The associations with viral control were independent of functional avidity of CD8(+) T cell responses elicited during early infection. Taken together, these data suggest that the next-generation of T-cell based HIV-1 vaccines should focus on strategies that can elicit CD8(+) T cell responses to multiple conserved epitopes of HIV-1.

Vaccine-induced HIV-specific CD8+ T cells utilize preferential HLA alleles and target-specific regions of HIV-1.

Most T cell-based HIV-1 vaccine candidates induce responses of limited breadth for reasons that are unclear. We evaluated vaccine-induced T-cell responses in individuals receiving an HIV-1 recombinant adenoviral vaccine. Certain HLA alleles (B27, B57, B35, and B14) are preferentially utilized to mount HIV-specific responses, whereas other alleles (A02 and B07) are rarely utilized (P < 0.001). This preference seems due to 4 following factors individually or in combination: higher affinity of specific peptides to specific HLA alleles; higher avidity of T-cell receptor; HLA and peptide interaction; and/or higher surface expression of certain HLA. Thus, HLA immunodominance plays a substantial role in vaccine-induced T-cell responses.

Protective HIV-specific CD8+ T cells evade Treg cell suppression.

Specific human leukocyte antigens (HLAs), notably HLA-B*27 and HLA-B*57 allele groups, have long been associated with control of HIV-1. Although the majority of HIV-specific CD8(+) T cells lose proliferative capacity during chronic infection, T cells restricted by HLA-B*27 or HLA-B*57 allele groups do not. Here we show that CD8(+) T cells restricted by 'protective' HLA allele groups are not suppressed by T(reg) cells, whereas, within the same individual, T cells restricted by 'nonprotective' alleles are highly suppressed ex vivo. This differential sensitivity of HIV-specific CD8(+) T cells to T(reg) cell-mediated suppression correlates with their expression of the inhibitory receptor T cell immunoglobulin domain and mucin domain 3 (Tim-3) after stimulation with their cognate epitopes. Furthermore, we show that HLA-B*27- and HLA-B*57-restricted effectors also evade T(reg) cell-mediated suppression by directly killing T(reg) cells they encounter in a granzyme B (GzmB)-dependent manner. This study uncovers a previously unknown explanation for why HLA-B*27 and HLA-B*57 allele groups are associated with delayed HIV-1 disease progression.