A case report serves as a reminder that such infection does occur, sometimes with fatal consequences. Seronegative HIV infection has been described previously but is quite unusual. In this brief report from Portugal, investigators described the phylogenetic analysis of a virulent HIV strain that resulted in a patient’s rapid progression to AIDS and death. The patient was a previously healthy 20-year-old heterosexual man who presented with fatigue and weight loss. Testing for infectious diseases, including serologic assays to detect antibodies to HIV-1 and HIV-2, provided no answers. Within 3 months, the patient developed oropharyngeal candidiasis, and his CD4 count dropped to 232 cells/mm3. HIV serology continued to be negative, even when his CD4 count dropped further, to 52 cells/mm3. Serum p24 antigen levels and plasma viral load were consistent with HIV infection. Within 6 months of his original presentation, he died of AIDS. Immediately before symptom onset, the patient had a 3-month relationship with a woman who was a sex worker and injection-drug user. She, too, experienced an aggressive course of disease, presenting with a CD4 count of 40 cells/mm3 and succumbing to AIDS within 21 months. In her case, serologic testing did reveal HIV infection. Phylogenetic testing confirmed that both patients were infected with a B/G recombinant variant that resembled a strain previously detected among injection-drug users in Spain and Portugal. Based on the presence of a heterogeneous virus population in the woman and a single virus population (all CCR5-tropic) in the man, researchers determined that transmission occurred from the woman to the man. Comment: This case report serves as a reminder that when patients with symptoms of HIV infection have negative results on antibody tests, we should pursue additional virus-specific tests (such as viral load). HIV-infected individuals can be seronegative for a number of reasons, including seroreversion, late seroconversion, evaluation during the window period, and defects in the immune system that prevent development of a humoral response to infection. Also notable in this report is the finding that a genetically uniform population of CCR5-tropic variants can cause rapidly progressive, fatal HIV infection, a course generally thought to be associated with CXCR4-expressing variants.Published in HIV/AIDS Clinical Care November 23, 2009