Certain histocompatibility leukocyte antigen (HLA) alleles are associated with improved clinical outcomes for individuals infected with human immunodeficiency virus type 1 (HIV-1), but the mechanisms for their effects remain undefined. An early CD8؉ T-cell escape mutation in the dominant HLA-B57-restricted Gag epitope TW10 (TSTLQEQIGW) has been shown to impair HIV-1 replication capacity in vitro. We demonstrate here that this T 242 N substitution in the capsid protein is associated with upstream mutations at residues H 219 , I 223 , and M 228 in the cyclophilin A (CypA)-binding loop in B57؉ individuals with progressive disease. In an independent cohort of epidemiologically linked transmission pairs, the presence of these substitutions in viruses encoding T 242 N was associated with significantly higher plasma viremia in donors, further suggesting that these secondary mutations compensated for the replication defect of T 242 N. Using NL4-3 constructs, we illustrate the ability of these CypA loop changes to partially restore replication of the T 242 N variant in vitro. Notably, these mutations also enhanced viral resistance to the drug cyclosporine A, indicating a reduced dependence of the compensated virus on CypA that is normally essential for optimal infectivity. Therefore, mutations in TW10 allow HIV-1 to evade a dominant early CD8 ؉ T-cell response, but the benefits of escape are offset by a defect in capsid function. These data suggest that TW10 escape variants undergo a postentry block that is partially overcome by changes in the CypA-binding loop and identify a mechanism for an HIV-1 fitness defect that may contribute to the slower disease progression associated with HLA-B57.
The sequence diversity of human immunodeficiency virus type 1 (HIV-1) represents a major obstacle to the development of an effective vaccine, yet the forces impacting the evolution of this pathogen remain unclear. To address this issue we assessed the relationship between genome-wide viral evolution and adaptive CD8؉ T-cell responses in four clade B virus-infected patients studied longitudinally for as long as 5 years after acute infection. Of the 98 amino acid mutations identified in nonenvelope antigens, 53% were associated with detectable CD8؉ T-cell responses, indicative of positive selective immune pressures. An additional 18% of amino acid mutations represented substitutions toward common clade B consensus sequence residues, nine of which were strongly associated with HLA class I alleles not expressed by the subjects and thus indicative of reversions of transmitted CD8 escape mutations. Thus, nearly two-thirds of all mutations were attributable to CD8 ؉ T-cell selective pressures. A closer examination of CD8 escape mutations in additional persons with chronic disease indicated that not only did immune pressures frequently result in selection of identical amino acid substitutions in mutating epitopes, but mutating residues also correlated with highly polymorphic sites in both clade B and C viruses. These data indicate a dominant role for cellular immune selective pressures in driving both individual and global HIV-1 evolution. The stereotypic nature of acquired mutations provides support for biochemical constraints limiting HIV-1 evolution and for the impact of CD8 escape mutations on viral fitness.
Despite limited data supporting the superiority of dominant over subdominant responses, immunodominant epitopes represent the preferred vaccine candidates. To address the function of subdominant responses in human immunodeficiency virus infection, we analyzed cytotoxic T lymphocyte responses restricted by HLA-B*1503, a rare allele in a cohort infected with clade B, although common in one infected with clade C. HLA-B*1503 was associated with reduced viral loads in the clade B cohort but not the clade C cohort, although both shared the immunodominant response. Clade B viral control was associated with responses to several subdominant cytotoxic T lymphocyte epitopes, whereas their clade C variants were less well recognized. These data suggest that subdominant responses can contribute to in vivo viral control and that high HLA allele frequencies may drive the elimination of subdominant yet effective epitopes from circulating viral populations.
The predictability of virus–host interactions and disease progression in rapidly evolving human viral infections has been difficult to assess because of host and genetic viral diversity. Here we examined adaptive HIV-specific cellular and humoral immune responses and viral evolution in adult monozygotic twins simultaneously infected with the same virus. CD4 T cell counts and viral loads followed similar trajectories over three years of follow up. The initial CD8 T cell response targeted 17 epitopes, 15 of which were identical in each twin, including two immunodominant responses. By 36 months after infection, 14 of 15 initial responses were still detectable in both, whereas all new responses were subdominant and remained so. Of four responses that declined in both twins, three demonstrated mutations at the same residue. In addition, the evolving antibody responses cross-neutralized the other twin's virus, with similar changes in the pattern of evolution in the envelope gene. These results reveal considerable concordance of adaptive cellular and humoral immune responses and HIV evolution in the same genetic environment, suggesting constraints on mutational pathways to HIV immune escape.
This chapter discusses areas of law relevant to mental health clinicians working with juveniles. Clinicians must be aware of the law in the specific jurisdictions in which they practice. The chapter provides an overview of several areas of law that clinicians are likely to encounter in their professional practice with juveniles, including legal constructs concerning the relationship between juveniles and their parents, guardianships, custody considerations in divorce cases, decision making on behalf of juveniles, and separate provisions for juveniles in the criminal justice system. It discusses the state’s interest in promoting the healthy development and protection of maltreated juveniles, shaping the provision of clinical care or education, and providing protections for juveniles with disabilities. Intended as a guide for clinical care providers, the chapter considers the differences between clinical and forensic roles and strongly cautions clinicians to avoid blurring these roles, which involve distinctly different responsibilities and rules.
Malingering is the intentional feigning, induction, or exacerbation of symptoms to achieve a conscious, tangible goal; factitious disorder is the intentional manipulation of symptoms to achieve the subconscious goal of assuming the sick role. These disorders impose great costs in terms of dollars spent, inappropriate diversion of resources to unnecessary clinical care, and negative effects on clinicians faced with patient deception. They challenge the assumption that patients provide accurate histories and accounts of their symptoms and are motivated to address the symptoms and concerns that they report. Malingering and factitious disorder are typically diagnoses of exclusion. Signs of a deception syndrome include numerous prior hospital admissions and emergency department visits and a history of suspected deception. Evaluations require careful history taking and physical examination; prudent use of studies, tests, and consultation; gathering of collateral information; thorough review of available records; and monitoring of the patient’s behavior in the medical setting.
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