Drug-resistant virus tracked through 3 men

Transmission chain runs from 1994 to 1998

Clinicians and researchers in Birmingham, UK, have found evidence that AZT-resistant HIV-1 was sequentially transmitted through three individuals over a four-year period.

"I think this is the first time that the secondary sexual transmission of drug-resistant HIV has been proven," says Stephen Taylor, MD, a doctor and clinical research fellow who treats HIV patients at Birmingham Heartland Hospital in the United Kingdom. "Sequential transmission has always been theoretically possible, and this case confirms the theory," Taylor says. "What we’re showing here is that resistance can not only be transmitted from one person to another, but that the second person can subsequently transmit the same resistant virus to others."

The transmission chain was discovered while a patient Taylor calls Patient B was being treated at the clinic. During this time, Patient B’s partner, Patient C, was discovered to have seroconverted, Taylor says. "Because I knew Patient C’s partner had been on medications, we did resistance testing, and that’s how we picked up that he had unusual mutations," Taylor explains. "Then we found that Patient B had identical mutations."

Sexual history proves crucial

When investigators checked Patient B’s blood samples from 1994, when Patient B first tested positive, they discovered that his very first blood sample already had five AZT mutations, which suggested that he had been infected with a resistant virus, because he hadn’t yet been on any antiretroviral medications at that point, Taylor says. "Then we tested blood samples from 1997 and 1998, and found that the same resistant virus persisted for a four-year period despite several changes in therapy," Taylor says.

The blood samples from Patient C, taken in 1998, showed that he had seroconverted with four of the original five AZT mutations. The next step was to find the original source of the drug-resistant mutations. Through obtaining a sexual history, investigators learned that another patient, called Patient A, had been a monogamous sexual partner of Patient B’s until Patient A’s death in 1995. Patient A had tested HIV-positive in 1991 and had been treated with AZT monotherapy. Blood samples from Patient A demonstrated five drug-resistant mutations, Taylor says.

After Patient A died, Patient B had become sexual partners with Patient C, who had seroconverted in 1998. Patient B, while receiving highly active antiretroviral therapy in recent years, had not been treated with drugs prior to 1997, and he never received AZT, Taylor says. "He received stavudine and lamivudine in 1997, but the blood sample that was checked for mutations was from 1994," Taylor adds.

Investigators analyzed the mutations and found that evidence of sequential transmission was supported by both epidemiological and phylogenetic evidence. The specific reverse transcriptase drug-resistance-associated mutations found in the three different men were M41L, E44D, L210W, and T215D.1

Through the phylogenetic analyses, investigators proved that the viruses were truly related and likely came from a single source, Taylor says. "What brought our attention to Patient C is that he had a mutation called T215D, and that is what we call a reversion mutation," Taylor explains. "This mutation is sometimes seen in people infected with AZT-resistant virus."

Another implication from the transmission study is that resistant virus can persist through generations and is more virologically "fit" than previously theorized, Taylor says. The study’s evidence that four out of the original five mutations were transmitted intact from Patient A to Patient B to Patient C over four years suggests that despite their possible impaired fitness, these resistant viruses are certainly fit enough to be sexually transmitted and subsequently cause disease, he adds.

"We also looked at virus in blood and semen of Patient B, and found that the transmitted virus was more closely related to the virus found in the genital tract than the virus found in the blood, which makes sense," Taylor says. "This is a proof of the principle that drug-resistant viruses can persist and be transmitted from one person to the next and go through multiple generations, which is of concern for newly infected individuals."

Reference

1. Taylor S, Cane P, Xu L, et al. Identification of a transmission chain of HIV-1 containing drug resistance-associated mutations. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle; Feb. 25-28, 2002. Poster 374.