Elsevier

Clinical Immunology

Volume 137, Issue 2, November 2010, Pages 199-208
Clinical Immunology

Extremely prolonged HIV seroconversion associated with an MHC haplotype carrying disease susceptibility genes for antibody deficiency disorders

https://doi.org/10.1016/j.clim.2010.07.003Get rights and content

Abstract

Severe immunodeficiency during primary human immunodeficiency virus (HIV) infection is unusual. Here, we characterized viral and immunological parameters in a subject presenting with Pneumocystis jirovecii pneumonia in the setting of prolonged primary HIV illness and delayed seroconversion. HIV antibody was only detected by enzyme-linked immunosorbent assay 12 months after presentation, and Western blot profiles remain indeterminate. Isolated virus was of R5 phenotype, exhibited poor viral fitness, but was otherwise unremarkable. Analysis of HIV antibody isotypes showed failure to mount a detectable HIV IgG response over nearly 2 years of infection, in particular IgG1- and IgG3-specific responses, despite normal responses to common infections and vaccines. Genetic analysis demonstrated homozygosity for part of an MHC haplotype containing susceptibility genes for common variable immunodeficiency (CVID) syndrome and other antibody deficiency disorders. Thus, a primary disorder of specific antibody production may explain exceptionally slow antibody development in an otherwise severe seroconversion illness. This highlights the need for multiparameter testing, in particular use of a fourth generation HIV test, for confirming HIV infection and underscores the importance of host factors in HIV pathogenesis.

Introduction

Infection with human immunodeficiency virus (HIV) frequently causes seroconversion illness characterized by fever, rash and lymphadenopathy, usually lasting less than 2 weeks although durations of up to 10 weeks have been reported [1]. Modest declines in CD4+ T-cell count during seroconversion are common but only 7% of seroconverters have CD4+ T-cell counts below 300 cells/μl [1], and severe immunosuppression is unusual. Consequently, AIDS defining illnesses (ADIs) are rare during seroconversion. However, approximately 2% of patients experience esophageal candidiasis [2], and ADIs including Pneumocystis jirovecii pneumonia [3], cryptosporidiosis [4], herpes oesophagitis [5] and cytomegalovirus colitis [6] have been reported during seroconversion. In addition, HIV-related complications can be present such as retinopathy [7], nephropathy [8] and neurological problems including meningoencephalitis, Guillain–Barre syndrome and cranial nerve palsies [1].

Antibody tests for HIV are extremely sensitive, detecting most infections within 4 weeks of infection [9] and essentially all by 3 months [10]. We previously described a subject with Kaposi's sarcoma who remained HIV seronegative for > 4 years by conventional testing despite seropositivity to HIV gp41 and Nef by enzyme-linked immunosorbent assay (EIA) [11]. We now report a 45-year-old man who experienced atypical seroconversion illness with P. jirovecii pneumonia and exceptionally slow HIV seroconversion. We undertook a series of virological, immunological and genetic studies to better understand the role of the virus and host contributing to rapid disease progression and atypical seroconversion in this subject.

Section snippets

Ethics statement

Written informed consent was obtained from the subject, and experiments were conducted according to guidelines endorsed by the Monash Medical Center institutional review board which approved this study, and guidelines described in the Australian National Statement on Ethical Conduct in Research Involving Humans. The study subject has read the manuscript and gave written consent for publication.

Western blot and isotype-specific EIA

Isotype-specific Western blots and anti-p24 and anti-gp120 isotype-specific EIA's were performed as

Clinical description

The subject is a 45-year-old man who presented initially in March 2005 with fever, sweats and severe sore throat and was prescribed amoxicillin/clavulanic acid, then amoxicillin, without benefit. Additional symptoms of lethargy and nausea ensued. Blood tests in June 2005 showed mild neutropenia (1.6 × 109/l), lymphopenia (0.8 × 109/l) and thrombocytopenia (141 × 109/l) and mild transaminitis (ALT 72 U/l, AST 54 U/l). Over 4 months of illness the subject experienced weight loss of 25 kg. Examination by

Discussion

We describe a patient with P. jirovecii pneumonia in the setting of a prolonged primary HIV illness and an exceptionally long HIV seroconversion (over 12 months), who was homozygous for part of an MHC haplotype that contains susceptibility genes for CVID. More prompt p24 antigen and viral load testing would have diagnosed this infection earlier, in particular the sensitive 4th generation HIV tests currently available for screening [30], [31]. HIV WB reactivity showed very slow development, with

Conclusions

In summary, our patient's presentation had two unusual aspects: he developed P. jirovecii pneumonia in the setting of a prolonged primary HIV illness, and had an exceptionally delayed seroconversion. Viral studies revealed a poorly replicating virus but with few other unusual characteristics. His failure to mount detectable IgG1 and IgG3 responses over nearly two years of illness probably reflected a primary disorder of antibody production, and HLA typing showed that he was homozygous for part

Acknowledgments

Highly purified HIV-1SF2 gp120 derived from CHO cells, used for the anti-gp120 EIA, was kindly provided by Dr. N Haigwood (Seattle Biomedical Research Institute, Seattle, WA, U.S.A.). This study was supported, in part, by a program grant from the Australian National Health and Medical Research Council (NHMRC) to SMC (358399), and grants from the Australian NHMRC to PRG (433915) and DAM (502617). PRG is the recipient of an Australian NHMRC Level 2 Biomedical Career Development Award. The authors

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