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HIV Compartmentalization in Central Nervous System During Acute Infection
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Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle
Mark Mascolini
Deep sequencing showed that HIV can enter the central nervous system (CNS) in the first days of infection and begin evolving differently there than in plasma, though such compartmentalization was rare in this small study in Thailand [1]. In the person with compartmentalization, one minor HIV variant made up 15% to 23% of virus in plasma but 42% to 50% of virus in cerebrospinal fluid (CSF).
HIV readily enters distinct anatomic compartments. Because subsequent migration between compartments can be restricted, HIV can evolve differently in different compartments. Researchers recognize this compartmentalization as an obstacle to HIV cure. Single-genome sequencing has confirmed CNS compartmentalization during early and chronic infection, but these studies involve people infected for more than 4 months.
A previous study of 10 people infected for a median of 20 days in the SEARCH010/RV254 protocol [2] found no evidence of CNS compartmentalization using HIV env single-genome amplification, but the sampling depth of single-genome amplification is limited. US Military HIV Research Program investigators conducted a new analysis to explore HIV compartmentalization in CSF of SEARCH010/RV254 participants using targeted deep sequencing. The study aimed to search for minor HIV variants and drug-resistant mutations in CSF and blood.
The analysis involved 13 antiretroviral-naive people with acute HIV (3 in Fiebig stage II, 6 in stage III, 3 in stage IV, and 1 in stage V). All had a viral load above 10,000 copies in paired plasma and CSF samples. Two of 13 participants were women, and age ranged from 22 to 45 years. They had been infected with HIV for an estimated 15 to 32 days. The study focused on the PR and RT regions of the HIV pol gene. The targeted deep sequencing used had a lower detection limit of 0.5% for minor variants.
Deep sequencing showed that 8 of 13 study participants had been infected with a single transmitted/founder (T/F) virus and had no evidence of compartmentalization between plasma and CSF. Five participants had infection established by multiple T/F viruses, and 1 of these 5 (8% of the 13) had plasma/CSF compartmentalization.
The study participant with compartmentalized HIV was a 22-year-old man in Fiebig stage II who had been infected for an estimated 19 days before sampling. His CD4 count stood at 165 and his viral load at 6.71 log10 in plasma and 6.61 log10 in CSF (both more than 5 million copies).
The researchers detected no major antiretroviral resistance in any study participants, while 6 participants had minor drug-resistance mutations. The participant with compartmentalization had no major or minor detectable mutations. However, he had a minor T/F variant circulating at low frequencies in plasma (15% to 23%) but high frequencies in CSF (42% to 50%). In the whole study group, drug resistance mutations profiles did not differ between plasma and CSF according to the Stanford University HIV Drug Resistance Database.
The investigators conclude that their study "provides evidence, for the first time, that CNS HIV-1 compartmentalization can occur as early as acute HIV infection, within days of exposure, though this early compartmentalization onset is uncommon."
References
1. Sirijatuphat R, Fletcher JL, Sanders-Buell E, et al. Deep sequencing reveals rare CNS compartmentalization in acute HIV-1 infection. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 71.
2. US Military HIV Research Program. A focus on acute infection.
http://www.hivresearch.org/news/focus-acute-infection-studies
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