HUman Retroviruses: HTLV & HIV

Question 1

Retroviruses

Answer 1

• Enveloped, single stranded (+) RNA viruses
• Contain reverse transcriptase enzyme, which converts viral RNA into DNA that integrates into the host chromosome
• Not transmissible through air, dust or normal conditions but requires intimate contact
• Two major representatives of retroviruses
• Oncoretroviruses (HTLV-I and HTLV-II)
• Lentiviruses (HIV-1 and HIV-2)

Question 2

Retroviruses - Oncoretroviruses HTLV 1 and HTLV 2

Answer 2

• Both HTLVs infect CD4+ T-lymphocytes
• They do not kill cells but transform the cells to produce new virus indefinitely
• Can transduce growth promoting genes called oncogenes partly responsible for malignancies

Question 3

HTLV 1 causes…

Answer 3

Human T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia and lymphoma (ATLL) mainly in Japan, Africa and Caribbean.

Question 4

HTLV 2 is ssociated with…

Answer 4

Human T-lymphotropic virus type II (HTLV-II) is associated with hairy cell leukemia

Question 5

Retroviruses - Lentiviruses

Answer 5

• Slow disease causing viruses •Human immunodeficiency virus; type 1 (HIV-1) and type 2 (HIV-2), the causative agents of acquired immunodeficiency syndrome (AIDS)
• Major cause of AIDS worldwide is HIV-1
• HIV infects and kills specifically CD4+ T cells
• Also infects monocytes/macrophages, dendritic cells, Langerhans cells, microglial cells, etc.
• May persist for years in a clinical latency state in the presence of viremia
• Productive infection results in full blown disease, AIDS

Question 6

Structure of Retroviruses

Answer 6

Question 7

The 3 virus specific essential enzymes

Answer 7

1. reverse transcriptase (RT)
2. protease (PR)
3. integrase (IN)

are packaged in the virus particle

Question 8

Answer 8

Question 9

Answer 9

Question 10

Retroviral Life Cycle

Answer 10

Question 11

HIV Life Cycle - Virus Entry

Answer 11

Question 12

CXCR4 is expressed at high levels on [] and low levels on [], whereas CCR5 is expressed at high levels on [] and low levels on [].

Answer 12

CXCR4 is expressed at high levels on T-cells and low levels on macrophages, whereas CCR5 is expressed at high levels on macrophages and low levels on T-cells.

Question 13

HIV-1 that interacts with CD4 and CXCR4 is called [] and CD4 and CCR5 is called [] virus.

Answer 13

HIV-1 that interacts with CD4 and CXCR4 is called X4 (lympho-tropic) and CD4 and CCR5 is called R5 (macrophage-tropic) virus.

Question 14

[] establishes infection in both macrophages and T-cells, whereas [] only in T-cells.

Answer 14

R5 establishes infection in both macrophages and T-cells, whereas X4 only in T-cells.

•R5 is transmitted from person-to-person and mother-to-child

Question 15

The 3 Activities of reverse transcriptase enzyme:

Answer 15

1. Viral genome (RNA) is converted cDNA by virion associated reverse transcriptase enzyme (RNA dependent DNA polymerase)
2. followed by removal of RNA (RNase H) and
3. synthesis of double stranded DNA (DNA dependent DNA polymerase)

•This results in a linear dsDNA molecule, which then circularizes and forms preintegration complex.

Question 16

Migration to the Nucleus

Answer 16

•The dsDNA with pre-integration complex migrates to the nucleus.

Question 17

Intergration

Answer 17

• Once, the double stranded DNA enters the nucleus, it then integrates into the host chromosome at random sites.
• This process is carried out by viral protein integrase.
• The viral genome called provirus becomes a part of cellular genome and replicates as long as the infected cell divides. HIV can also replicate in resting cells.

Question 18

transcription

Answer 18

• LTR sequences contain promoter, enhancer, and other signals required for transcription of viral genes by host RNA polymerase II
• Full length genomic RNA and several species of spliced mRNAs are produced
• The predominant spliced mRNA encodes envelope glycoproteins
• HIV generates a series of spliced mRNAs that encode viral regulatory proteins which are involved in transcriptional and posttranscriptional events

Question 19

Translation

Answer 19

• The structural capsid proteins are translated as polyproteins and processed into individual mature proteins by viral encoded protease
• The regulatory proteins are encoded by spliced mRNAs, which regulate viral gene expression, assembly, mRNA stability and infectivity

Question 20

Viral Assembly and Release

Answer 20

• Viral assembly takes place after the proteins are synthesized
• Once the virus is assembled it buds through plasma membrane

Question 21

Answer 21

Question 22

HTLV 1 and 2 Receptor

Answer 22

• Not biochemically identified
• Found in a wide variety of human cells
• Syncytia formation demonstrated
• HTLV-I and II utilize the same receptor
• HTLV is able to infect a number of cell types

Question 23

HTLV 1 and 2 Transmission

Answer 23

• Blood to blood transmission
• Homosexual and heterosexual intercourses
• Mother to child (prepartum, partum, and postpartum)
• HTLV is not transmitted through cell free fluids

Question 24

HTLV 1

Answer 24

• HTLV associated myelopathy, CSF contains anti-HTLV-I
• Show lymphocytic pleocytosis, Proteins level elevated
• Hematologic malignancies,
• B-cell chronic lymphocytic leukemia
• Immunosuppression

Question 25

HTLV 2

Answer 25

•Hairy cell leukemia of B-cell origin found as Tcell origin called T-cell variant hairy cell leukemia

Question 26

HTLV Diagnosis

Answer 26

* Antibody by ELISA, cross reactivity with HTLV-I & II * PCR, specifically differentiates between HTLV-I & II

Question 27

HTLV Treatment

Answer 27

* No specific treatment * Deoxycoformycin is an effective drug * Interferon treatment * Recombinant vaccines are being tested in animals

Question 28

Transformation by Oncoretroviruses

Answer 28

1. The acute transforming viruses acquire a cellular gene (oncogene) that results in loss of normal growth control upon expression. Seen in animal viruses 2. The second mechanism is called insertional mutagenesis caused by integration of a retrovirus in the vicinity of particular cellular genes. Seen in animal viruses 3. The third mechanism is the continual expression of the viral Tax gene that activates viral transcription and expression of cellular genes (possibly protooncogenes) resulting in transformation. This mechanism allows HTLV to transform cells. T cell Leukemia in HTLV 1!