Retroviruses

Retroviruses

I Retroviridae: General Features

• Midsized viruses with an enveloped capsid containing two copies of a single-stranded (+) RNA genome, transfer RNA (tRNA), reverse transcriptase, integrase, and protease.

Retroviruses are enveloped and must carry reverse transcriptase, integrase, and protease enzymes to initiate replication.

• Two human pathogens—human immunodeficiency virus (HIV) and human T lymphotropic virus (HTLV)—are retroviruses.

A Retroviral genes

1. All retroviral genomes contain three genes—gag, pol, and env—and are flanked by long-terminal repeats (Table 26-1).

TABLE 26-1

Retrovirus Genes and Their Function

Gene	Virus	Function
gag	All	Group-specific antigen: core and capsid proteins
int	All	Integrase
pol	All	Polymerase: reverse transcriptase, protease, integrase
pro	All	Protease
env	All	Envelope: glycoproteins
tax	HTLV	Transactivation of viral and cellular genes
tat	HIV-1	Transactivation of viral and cellular genes
rex	HTLV	Regulation of RNA splicing and promotion of export to cytoplasm
rev	HIV-1	Regulation of RNA splicing and promotion of export to cytoplasm
nef	HIV-1	Alteration of cell activation signals; progression to AIDS (essential)
vif	HIV-1	Virus infectivity, promotion of assembly, blocks a cellular antiviral protein
vpu	HIV-1	Facilitates virion assembly and release, decrease of cell surface CD4
vpr (vpx*)	HIV-1	Transport of complementary DNA to nucleus, arresting of cell growth
LTR	All	Promoter, enhancer elements

HIV, human immunodeficiency virus; HTLV, human T lymphotropic virus; LTR, long-terminal repeat (sequence).

From Murray PR, Rosenthal KS, Pfaller MA: Medical Microbiology, 6th ed. Philadelphia, Mosby, 2009, Table 64-2.

Simple retroviruses have three genes (gag, pol, env), complex retroviruses (like HIV) have more genes.

• Each gene encodes a polyprotein, which is cleaved to yield the final gene products.

a. gag → nucleocapsid proteins

b. pol → enzymes (reverse transcriptase, integrase, and protease)

c. env → envelope glycoproteins

2. Complex retroviruses, such as HIV, have several other genes encoding auxiliary and regulatory proteins (e.g., nef, tat, and rev)

B Key HIV proteins (Fig. 26-1)

26-1 Genome structure of human retroviruses: (A) HTLV-1 and (B) HIV. The basic retrovirus genome consists of the long terminal repeat (ltr) group–specific antigen (capsid proteins)(gag)-enzymes(polymerase, integrase, protease)(env) and the glycoproteins (env). Complex retroviruses, such as HIV have additional proteins that enhance their virulence. These are described in Table 26-1. (Redrawn from Belshe RB: Textbook of Human Virology, 2nd ed. St Louis, Mosby, 1991. In Murray PR, Rosenthal KS, Pfaller MA: Medical Microbiology, 6th ed. Philadelphia, Mosby, 2009, Fig. 64-4.)

1. Major envelope glycoprotein consists of two associated proteins: an attachment protein (HIV gp120) and transmembrane fusion protein (HIV gp41) both cleaved from gp160 precursor.

2. Three enzymes are carried within the nucleocapsid: reverse transcriptase, integrase, and protease.

3. Matrix protein (HIV p17) forms a layer underlying the envelope.

4. Nucleocapsid protein (HIV p24) forms the outer layer of the virion core, and detection in blood indicates infection.

C Replication

• Replication cycle (Fig. 26-2)

26-2 The life cycle of human immunodeficiency virus (HIV). mRNA, messenger RNA.

1. Attachment and fusion

• Binding of viral gp120/gp41 to CD4 and a chemokine coreceptor is required for HIV infection of cells.

a. Preference for chemokine coreceptor genetically switches during disease from:

• Initial: CCR5—on macrophages, dendritic cells, and T cells

Later: CXCR4—on T cells

Initial HIV target cell expresses CD4 and CCR5 chemokine receptor on macrophages, dendritic cell, and T cell; later, HIV mutates and binds to T cells expressing CD4 and CXCR4.

2. Formation of HIV provirus

• Reverse transcriptase carried in the virion synthesizes a complementary DNA (cDNA) from viral genome, forming an RNA-DNA hybrid. The same enzyme then degrades the RNA strand and synthesizes a complementary DNA strand, forming double-stranded viral DNA.

a. Reverse transcriptase causes a high mutation rate in newly formed viral DNA.

• Viral integrase catalyzes integration of viral DNA into host nuclear DNA, forming provirus.

a. Provirus is part of host chromosome and vertically transmitted with host DNA and passed on to daughter cells.

Reverse transcriptase, integrase, and protease are enzymes critical to HIV replication and are major targets of drugs used in the treatment of HIV infection.

3. Viral messenger RNA (mRNA) and genome replication

• Host DNA-dependent RNA polymerase transcribes a full-length (+) RNA copy of the integrated genome and several shorter mRNA copies for individual proteins and polyproteins.

• After synthesis of viral proteins, nucleocapsids containing two copies of genome associate with glycoprotein modified plasma membrane and bud off.

• After budding, protease cleaves gag-pol polyprotein to produce mature (cone-shaped) nucleocapsid and functional integrase and reverse transcriptase enzymes.

D Genetic variation

HIV polymerase is error prone, and mutations produce new substrains.

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