Porth's Essentials of Pathophysiology, 4e

364

Infection and Immunity

U N I T 4

Integrase

CD4 + binding site

1

gp 120

Lipid membrane

gp 41

gp120

RNA

p 17 matrix

3

2

Reverse transcriptase

4

p 24 capsid

Viral polyprotein

5

6

Protease

7

Reverse transcriptase

8

A

B

FIGURE 16-8. (A) Structure of the human immunodeficiency virus (HIV). RNA, ribonucleic acid. (B) Life cycle of HIV-1. (1) Attachment of the HIV virus to CD4 + T-cell receptor; (2) internalization and uncoating of the virus with viral RNA and reverse transcriptase; (3) reverse transcription, which produces a mirror image of the viral RNA and double-stranded DNA molecule; (4) integration of viral DNA into host DNA using the integrase enzyme; (5) transcription of the inserted viral DNA to produce viral messenger RNA; (6) translation of viral messenger RNA to create viral polyprotein; (7) cleavage of viral polyprotein into individual viral proteins that make up the new virus; and (8) assembly and release of the new virus from the host cell.

T cells, the proviral cDNA may remain in the cytoplasm in a linear extrachromosomal form. The fifth step involves transcription of the double-stranded viral DNA to form a single-stranded messenger RNA (mRNA) with the instructions for building new viruses. Transcription involves activation of the T cell and induction of host cell transcription factors. Alternatively, the provirus may remain nontranscribed within infected cells for months or years, hidden from the host’s immune system and even from antiviral therapies. Long-lived reservoirs of HIV are established within the first month of acute infection. 46 These reservoirs of latent infected cells do not spontaneously produce virus unless activated. Their long life span constitutes one of the main barriers to HIV eradication by current antiviral therapies. The sixth step includes translation of the viral mRNA. During translation, ribosomal RNA (rRNA) uses the instructions in the mRNA to create a chain of proteins and enzymes called a polyprotein. These polyproteins contain the components needed for the next stages in the construction of new viruses. The seventh step is called cleavage. During cleavage, the protease enzyme cuts the

polyprotein chain into the individual proteins that will make up the new viruses. Finally, during the eighth step, the core proteins migrate to the cell membrane, where they acquire a lipid envelope that buds off from the cell membrane. Productive infections, associated with exten- sive viral budding, lead to cell death. 2 It is important to note that although HIV can infect resting cells, the initiation of transcription and viral replication occurs only when the infected cell is activated by exposure to antigens or cytokines. Within 72 hours of a transmission event, local virus replication occurs at the site of infection and the draining lymph nodes. 46 Infection becomes systemic by the end of the first week, as the virus disseminates to other lym- phoid tissue compartments. By day 10 after infection, most circulating CD4 + T cells either have been infected with or have interacted with HIV. The availability and rapid consumption of targets during this early period leads to massive viral replication, accounting in part for the high levels of viremia and genital shedding achieved by the end of the first month. Once infection has become truly systemic, viral loads grow exponentially, with a