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AIDS:
doi: 10.1097/QAD.0b013e328332d5e1
Research Letters

Rapid clinical progression to AIDS and death in a persistently seronegative HIV-1 infected heterosexual young man

Bártolo, Inêsa,b; Camacho, Ricardoc,d; Barroso, Helenaa,b; Bezerra, Victore; Taveira, Nunoa,b

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aUnidade dos Retrovírus e Infecções Associadas, Centro de Patogénese Molecular, Faculdade de Farmácia de Lisboa, Lisbon, Portugal

bCentro de Investigação Interdisciplinar Egas Moniz (CiiEM), Instituto Superior de Ciências da Saúde Sul, Caparica, Portugal

cLaboratório de Biologia Molecular, Centro Hospitalar Lisboa Ocidental, Lisboa, Portugal

dInstituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisboa, Portugal

eServiço de Medicina 1, Hospital Distrital de Santarém, Santarém, Portugal.

Received 30 July, 2009

Revised 2 September, 2009

Accepted 9 September, 2009

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Abstract

Seronegative HIV-1 infection has important implications for diagnosis and prevention. We describe a case of HIV-1 infection without seroconversion and fast progression to AIDS and death. Genetic and phylogenetic analysis indicated that the patient was infected with a CRF14_BG-like strain selectively transmitted by his seropositive sexual partner. The results suggest a massive infection with a highly aggressive CRF14_BG-like strain and/or the presence of an unidentified immunological deficiency that has prevented the formation of HIV-1-specific antibodies.

HIV infection is routinely diagnosed by the detection of specific antibodies in serum or plasma. This is not possible if the infected individuals do not produce HIV-specific antibodies [1–3] or in cases of infection with highly divergent HIV strains [4]. Here, we present the case of a patient infected with a CRF14_BG-like HIV-1 strain with very rapid progression to AIDS and death with persistently negative antibody tests.

Patient 98PTHEM103, a previously healthy 20-year-old heterosexual man, presented to Hospital de Santarém in September 1997 with a history of fatigue and weight loss. He had a normal lymphocyte count (3125/μl) and negative serology for hepatitis B virus, hepatitis C virus, human T cell lymphotropic virus (HTLV)-I, HTLV-II, cytomegalovirus, HIV-1 and HIV-2. On December 1997, he was diagnosed an oropharingeal candidiasis. He was still seronegative for HIV-1 and HIV-2. His total lymphocyte count was 232 cells/μl. In February 1998, after rapid clinical deterioration, he was hospitalized with fever, wasting syndrome, and oropharingeal candidiasis. Quantitative serum immunoglobulins were normal (IgA 4.7 g/l; IgM 1.5 g/l; IgG 12.2 g/l). HIV-1 and HIV-2 serology were negative by multiple enzyme immunoassay tests and western blot (Fig. 1). His CD4 cell count dropped to 52 cells/μl. Serum p24 antigen was positive (135 pg/ml) and plasma viral load was high (>8 × 106 copies/ml, Amplicor HIV Monitor kit; Roche, Basel, Switzerland). He died of AIDS on March 1998. His sole HIV risk factor was a 3-month (June to September 1997) sexual relationship with patient 98PTHEM104.

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Patient 98PTHEM104, a 21-year-old woman, was an intravenous drug user and sex worker. She presented at the hospital on May 1996 with extrapulmonary tuberculosis and oropharingeal candidiasis. She tested positive for HIV (Fig. 1). Her CD4 cell count was 40 cells/μl. In November 1996, she had an HIV-1 viral load measurement of 61 978 copies/ml and started antiretroviral therapy with indinavir, didanosine and zidovudine, which resulted in clinical and virological improvement. In September 1997, she attended the hospital with diarrhea, fever, oral candidiasis and peripheral neuropathy. She died of AIDS on February 1998.

Serological tests may yield false negative results in HIV-1 group N infections, or infection by a new and highly divergent HIV-1 variant [4]. There is also the possibility of infection by a particularly aggressive viral strain that may not permit the development of a host immune response. It is therefore important to analyze the genotype of the viruses from all seronegative HIV-1 infections. A nested PCR was performed to obtain a 409 bp fragment from the C2-V3 env region and a 582 bp fragment from the p17 gag region of viral isolates from both patients. Thermal cycling conditions for PCR and primers have been described previously [5]. For patient 98PTHEM103, PCR was done on chromosomal DNA extracted from sections of different postmortem tissues using a universal extraction method previously described [6]. For patient 98PTHEM104, serum collected in 1996 was the only available biologic material. Viral DNA suitable for PCR amplification was obtained by reverse transcription from RNA recovered from 200 μl of serum, as described [5]. PCR fragments were cloned into the pCR2.1 vector (Invitrogen, Carlsbad, California, USA) and sequenced. To determine virus subtype and investigate evolutionary relationships between the two isolates, maximum likelihood phylogenetic analyses was performed using the GTR+G model of nucleotide substitution, as described previously [5]. Tree searches were conducted in PAUP v4.0b10 using a nearest-neighbor interchange heuristic search strategy and bootstrap. The sequences have been assigned GenBank accession numbers GQ387120-GQ387157.

Both patients were infected with a B/G recombinant strain (B in env and G in gag) resembling HIV-1 CRF14_BG, a variant that was originally found in Portuguese and Spanish intravenous drug users (Fig. 1) [7,8]. Phylogenetic analysis indicated also that patient 98PTHEM104 was infected with a quasispecies evolving into two clearly separate branches, whereas patient 98PTHEM103 harbored a single virus population that was present in all tissues that were tested (Fig. 1). Some sequences from both patients clustered together in phylogenetic analysis with high bootstrap values (Fig. 1). This result is consistent with selective virus transmission from one patient to the other. Genotypic analysis of tropism with the Geno2pheno software [9] indicated that all virus isolates from patient 98PTHEM103 were CCR5. These results show that, in the absence of antibody pressure, CCR5 viruses may cause fatal infections and that CXCR4 viruses are not required for progression to AIDS. In contrast, only one strain from patient 98PTHEM104 was CCR5, with all the others being CXCR4. Interestingly, this CCR5 strain clustered with the 98PTHEM103 strains. Sequence divergence was higher in patient 98PTHEM104 than in patient 98PTHEM103, both in the env (13.3 vs. 1.9%) and gag (2.9 vs. 2.4%) genes. The low genetic diversity in the virus populations from patient 98PTHEM103 is consistent with a recent infection and the absence of immunologic pressure imposed on the viruses [10]. In contrast, the higher virus genetic diversity in patient 98PTHEM104 is consistent with a longer period of infection and immune competency [11]. We therefore conclude that patient 98PTHEM104 was the index case and that she possibly transmitted a highly virulent CCR5 virus to patient 98PTHEM103.

Rare cases of HIV-1 infected patients with clinical symptoms of AIDS but repeatedly negative for HIV antibody screening have been described [1–3]. There may be several reasons for negative HIV screening results in patients who are HIV-infected. Among host factors, the most well recognized is the window period, generally 20–25 days after infection, depending on the specific enzyme immunoassay reagents used [12]. Late seroconversions of up to 40 months after infection have been described [13,14]. Other host factors that could explain seronegative infection include profound hypoglobulinemia, B-cell functional defects and seroreversion [12,15]. This does not appear to be the case in patient 98PTHEM103 because he had negative results from antibody tests in all occasions and his immunological parameters were otherwise normal.

In conclusion, patient 98PTHEM103, a previously healthy individual, exhibited a fatal infection with the absence of an HIV-specific humoral response. The results suggest a massive infection with a highly aggressive CRF14_BG-like strain and/or the presence of an unidentified immunological deficiency that has prevented the formation of HIV-1-specific antibodies.

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Acknowledgements

The clinical and laboratorial contributions of Manuela Mafra and Sandra Bento for the early identification and study of these patients are gratefully acknowledged.

Author's contributions: N.T., R.C., and V.B. designed the research. N.T., R.C., V.B., I.B. and H.B. performed the research, interpreted the data and wrote the paper. All authors reviewed and accepted the final manuscript.

Financial Support: This work was supported by grant CRIA-CR3751 from Comissão Nacional de Luta Contra a SIDA, Portugal.

Human experimentation and ethical guidelines of each of the authors' institutions were followed in the conduct of the clinical research described in this paper.

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