Human Immunodeficiency Virus (HIV) infects cells by attaching to the CD4 receptor with its gp120 glycoprotein. It requires a co-receptor, CCR5 or CXCR4, for fusion and entry into the cell. Once inside, the viral RNA is converted to DNA by reverse transcriptase. The DNA integrates into the host genome with the help of integrase. The virus hijacks the cell's machinery to produce new viral proteins and RNA, which are assembled into new virus particles that bud from the cell.

1. Human Immunodeficiency Virus
1. Attachment
a. HIV remains asymptomatic during early stages of its infection. It is macrophage
tropic its early stages of infection while later it becomes T-Lymphocyte tropic.
b. HIV needs two receptors for its adsorption to the cell. One Major and other co-
receptor.
c. The major receptor for HIV binding is CD4. For Macrophage the co-receptor is CCR5
which is a chemokine receptor while for T lymphocyte the co-receptor is CXCR4.
d. HIV attached to receptor with the help of gp120 glycoprotein. Gp41 interacts with the
co-receptor.
2. Entry& Uncoating
a. gp120 – CD4 interaction exposes gp41 binding sites which then interacts with the co-
receptor.
b. The binding of gp41 leads to conformation changes that releases gp120 and causes
the hairpin bend in the two subunits of gp41 viz. HR1 (proximal to host cell
membrane) and HR2 (viral transmembrane subunit).
c. This causes the host cell membrane and viral membrane to fuse together following
entry of viral capsid inside the host cell.
d. Immediately after entry of viral capsid inside the cytoplasm of the host cell, the
matrix and capsid proteins get denatured by the proteolytic enzymes present in the
cytoplasm releasing the viral proteins and nucleic acid in the cytoplasm.

2. 3. Replication
a. Inside the cytoplasm, the viral proteins play a crucial role in replication of the virus.
b. The reverse transcriptase is the major enzyme encoded by the viral genome that
transcribes single stranded DNA from viral RNA. For this it uses host tRNAlys
as a
primer. It also has RNase H activity by which it dissociates RNA-DNA hybrid and
then uses its polymerase activity to synthesize the dsDNA of a virus.
c. The viral dsDNA has LTRs on both the ends. The dsDNA is then cut to form sticky
ends at the terminal ends and then transported to the nucleus by viral integrase (p32)
to integrate it with the host cell chromosome. At this stage the virus is called
Provirus.
d. Like a typical retroviral genome the HIV genome contains gag, pol and env gene and
may also contain onc gene.
e. The viral DNA forms proteins with the help of host transcription and translation
machinery.
f. tat (transcriptional transactivator) and rev (regulation of virion proteins) proteins are
essential in HIV replication. tat binds to TAR region and increases rate of
transcription by 1000 fold. rev binds to RRE to facilitate export of unspliced or
incompletely spliced viral RNAs from nucleus to cytoplasm.
g. The viral proteins nef, vif, vpu and vpr also play an important role in HIV replication.
Their functions are given in table below.
Proteins Functions
nef Negative factor, plays important role in host cell apoptosis, down
regulation of CD4 and MHC I
vif Virion infectivity factor required to synthesize infectious particles
vpu Viral Protein U, involved in proteolytic degradation of CD4
vpr Viral protein R, Nuclear import of pre-integration complex and G2 cell
cycle arrest

3. h. The ribosomes of cellular machinery translate viral mRNA into proteins. The gag,
env and pol genes are translated into large precursor polyproteins which are later
cleaved by protease.
Structural
Gene
Products Name of the protein
gag P17 Matrix protein
P24 Nucleo-capsid protein
P9
RNA binding nucleo-capsid protein
P7
pol P10 Protease
P15,P51 Reverse Transcriptase RNase H activity
P32 Integrase
env gp120 Glycoprotein
gp41 Glycoprotein (Trans-membrane) having HR1
(proximal to cell membrane) and HR2 (Viral trans-
membrane) subunits
i. gp120 and gp41 are attached to each other by non-covalent bonding. The genes of tat
overlap with the structural genes but in different ORFs. Their mRNAs are derived
from the alternate splicing of the structural genes mRNAs.
4. Maturation
The virion components are assembled at the budding sites located at the cellular plasma
membrane. Two copies of cellular plasma genome that contain the cellular replication
primer tRNAlys
are packed into virus.
5. Release
Mature viral particles are released outside the host cell by budding. It is thought that CD4
receptors of host cell may block the matured virions during release as they interact with
the gp120 of the virions. Viral protein nef is thought to play an important role in
inhibiting this interaction and releasing infectious virions.
*************