Which event occurs EARLIEST in the HIV replication cycle?

Correct answer: D. Reverse transcription of viral RNA into DNA

• A. Integration follows reverse transcription — the newly made DNA must exist before integrase can splice it into the host genome as a provirus. This step is the reason HIV infection is lifelong.
• B. Protease cleavage is one of the LAST steps, occurring during and after budding to convert immature non-infectious particles into mature infectious virions.
• C. Transcription of viral RNA from the integrated provirus occurs only after integration and uses host RNA polymerase II.
• D. CORRECT. Of the four listed, reverse transcription comes first. After gp120 binds CD4 and a co-receptor (CCR5 or CXCR4) and the viral envelope fuses with the cell membrane, the core enters the cytoplasm and reverse transcriptase converts single-stranded viral RNA into double-stranded DNA. This enzyme has no proofreading capacity, which is the reason HIV mutates so rapidly and why combination therapy is necessary.

Note: Sequence: attachment → fusion → uncoating → REVERSE TRANSCRIPTION → integration → transcription → translation → assembly → budding → protease maturation. Each step is a drug target, which is a reliable way to remember the order: entry inhibitors (maraviroc), NRTIs and NNRTIs (reverse transcription), integrase inhibitors (dolutegravir), protease inhibitors (ritonavir).