A 36-year-old woman comes to the clinic for follow-up of HIV infection. The patient was diagnosed with HIV approximately 15 years ago. She had been taking combination antiretroviral therapy until 5 months ago when she had a mental breakdown triggered by the sudden death of her husband. The patient's CD4+ T-lymphocyte count has been consistently >750/mm3, and her peripheral blood HIV RNA has been undetectable. However, repeat studies today show that her CD4+ count is now 310/mm3 and her HIV RNA is 8,212 copies/mL. Reactivation of HIV from which of the following reservoirs most likely explains this patient's viremia?
This patient with previously controlled chronic HIV infection has rebound viremia after stopping antiviral therapy (ART). This rebound viremia reflects reactivation of HIV from the latent viral reservoir. The latent reservoir can be considered in molecular and anatomical terms:
Molecular: Latent HIV exists primarily as a genomically integrated viral DNA (ie, a provirus), embedded randomly throughout the host nuclear genome. Insertion into the genome is accomplished by integrase and occurs during the earliest stages of infection (ie, within days of acute HIV).
Anatomical: A range of organs and cell types serves as depots for latently integrated HIV. The majority of the latent HIV resides within lymphoid tissues, especially the lymph nodes, lymphatic vasculature, and gut- and mucosa-associated lymphoid tissues (GALT and MALT). Other important anatomic/cellular reservoirs include the CNS (astrocytes, microglia) and lungs (alveolar macrophages).
Because reservoir cells may be long-lived (eg, brain astrocytes have extremely slow turnover), complete replacement of all infected cells is highly unlikely to occur within the patient's lifespan. ART can only suppress production and infective spread of new HIV particles; it cannot eliminate the latent reservoir.
Rebound of HIV viremia and subsequent propagation to new reservoir sites is therefore inevitable if ART is discontinued. For these reasons, HIV is presently a chronic and incurable condition, even after decades without detectable viremia.
(Choice A) HIV reactivates via transcription of proviral DNA by host RNA polymerase. Like all mRNAs in general, the newly transcribed HIV mRNA is intrinsically unstable (t1/2 of hours); it must be promptly translated into proviral polyproteins or packaged into the capsid as the viral genome. Because it is so short-lived, viral mRNA is not a latent reservoir.
(Choice C) Some human herpesviruses (eg, EBV) infect B lymphocytes, maintaining a latent reservoir in the form of circularized extrachromosomal (ie, episomal) viral DNA. In the setting of chronic HIV, uncontrolled EBV replication immortalizes B cells, leading to HIV-associated lymphomas.
(Choices D and E) Once assembled and released, mature HIV virus particles survive briefly (less than a day) before infecting new cells and/or being degraded. Due to their transient status, preassembled viral are not a molecular reservoir. Furthermore, even in uninfected individuals, circulating CD4+ T lymphocytes are short-lived, and this population of cells is replaced every 2 weeks.
Educational objective:
HIV reactivates from a permanent latent reservoir consisting of genomically integrated proviral DNA in lymphoid tissues.